Coarse-Grained Simulations of Macromolecules: From DNA To Nanocomposites

PC62CH26-de-Pablo ARI 25 February 2011 16:25
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Juan J. de Pablo
Department of Chemical and Biological Engineering, University of Wisconsin–Madison,
Madison, Wisconsin 53706; email: depablo@engr.wisc.edu
by University of Leeds on 06/23/13. For personal use only.
Annu. Rev. Phys. Chem. 2011. 62:555–74 Keywords

First published online as a Review in Advance on molecular simulations, polymers, copolymers, nanoparticles
January 10, 2011
The Annual Review of Physical Chemistry is online at Abstract

physchem.annualreviews.org
This review discusses multiscale modeling and simulations of macro-
This article’s doi: molecules and macromolecular systems in the context of two specific exam-
10.1146/annurev-physchem-032210-103458
ples. In the first, recent attempts to develop coarse-grained representations
Copyright c 2011 by Annual Reviews. of DNA are reviewed, and a discussion of recent predictions of such models
All rights reserved
is presented, particularly in the context of DNA melting and rehybridization.
0066-426X/11/0505-0555$20.00 The second example considers polymer nanocomposites; a review of recent
simulations is presented, with an emphasis on the description of entangle-
ments in such systems and new methods for the study of the segregation of
nanoparticles that arises in copolymers, in which composition heterogene-
ity can be used to control nanoparticle position and develop an increased
understanding of nanoparticle-polymer interactions.
555
INTRODUCTION
Multiscale modeling has come of age over the past decade. A number of reviews on hierarchical
modeling, coarse graining, and multiscale methods for soft matter have appeared over the past
several years (1–26). A broad range of topics has been covered, including proteins, glasses, mem-
branes, and polymers. The aim of this review is not to reproduce what can be found in existing
reviews, but to focus on polymeric systems whose function arises over relatively large scales or do-
mains and emerges from specific molecular-level considerations. For concreteness, the discussion
is centered on two specific classes of molecules or materials that have not been discussed before
in the context of a multiscale-modeling review and that represent new and promising trends in
the development of coarse-graining strategies. The first system discussed concerns DNA and its
mesoscale description; the main issue here is to capture the functionality of the molecule that
emerges from its sequence. The second system considered concerns composites of nanoparticles
and polymeric molecules—nanocomposites; the issue here is to understand and predict the be-
havior, structure, and directed assembly of the resulting nanocomposite that arises over relatively
long length scales. As shown below, as important as these systems are in science and technology,
their modeling remains in its infancy. The aim of the discussion that follows is to stimulate interest
in the modeling and simulation of functional materials, including DNA and nanocomposites, and
to provide readers with a starting point for further studies.

Beyond their scientific and technical relevance, DNA and nanocomposites represent a partic-
ularly useful choice for a discussion of modeling and simulation of macromolecules because they
each highlight a different set of needs and challenges. In the case of DNA, one seeks to develop
reduced models capable of describing the many functions of DNA. In the case of nanocomposites,
the challenge is to develop methods or approaches that enable the simulation of these materials,
particularly under deformation.
At the outset I emphasize that the review that follows is not comprehensive; the issues and the
examples discussed here are biased by my current interests. Whenever possible, however, I have
made reference to a number of recent, authoritative reviews and texts on multiscale or hierarchical
modeling of soft materials that offer readers a broader perspective than that presented here.
COARSE-GRAINED MODELS OF DNA

Several models of DNA are available in the literature. These range from fully atomistic repre-
sentations, in which all atoms (including those of the solvent) are considered explicitly, to highly
coarse grained, in which collections of several hundred atoms are represented by a few spherical
beads connected by worm-like chain springs. Although a complete description in terms of all
atomic coordinates would at first glance appear desirable, as more chemical detail is included in a
model the computational requirements associated with its solution increase significantly, thereby
restricting severely the length scales and timescales amenable to study. The challenge is therefore
to include just enough detail in a model to capture the physics that are responsible for DNA’s
relevance in biology (27).
Atomistic models based on force fields such as CHARMM (28) and AMBER (29) provide
the highest degree of detail. Recent reviews have presented a useful perspective of the uses and
limitations of such models (30–32). Such reviews and recent calculations show that comprehensive
studies of long DNA molecules, including hybridization and packaging, continue to be well beyond
the reach of fully atomistic representations.
At the other end of the spectrum of length scales, e.g., for study of full genomic DNA, several
models have been proposed and have shed considerable light onto the dynamical behavior of DNA
556 de Pablo
in various environments (33–47). The persistence length of DNA is in the vicinity of 50 nm; such
models are relatively coarse in that they represent several dozen persistence lengths with spherical
beads connected to one another by a worm-like chain spring. In spite of their low resolution, they
yield results in excellent agreement with experimental data for diffusion, structural relaxation, and
behavior under different flow fields for bulk and confined DNA.
For many applications of interest, however, the approaches mentioned above, either atomistic
or bead/spring, are inadequate. Let us consider, for example, the formation of structured materials
through DNA-enabled colloidal assembly. In that case linker DNA (48) comprising on the order
of 10 to 30 nucleotides is used to bind nanoparticles; to improve assembly strategies, it is of
interest to understand hybridization for such molecules. Or let us consider the packaging of DNA
in chromatin, a fundamental element of biology in which a DNA of approximately 150 base pairs
must tightly wrap around a small protein complex to form the nucleosome (49). In each of these
applications, relevant phenomena or processes occur on length scales and timescales commensurate
with the contour length of the molecules and their longest relaxation time, but essential effects such
as hybridization or melting occur at a local level. The need for an intermediate-level description
of DNA has led to the development of mesoscale models of DNA (47, 50–62). Such models have
been successful in reproducing distinct features of DNA but do not provide a comprehensive
description of melting, hybridization, mechanical properties, and electrostatic effects within one
representation.
Recently, we have proposed a coarse-grained representation of DNA to do just that. Below
we describe such a model, some of its predictions, and its limitations. As shown in Figure 1, the
model represents each nucleotide using three interaction sites, and so we refer to it as 3SPN (three
sites per nucleotide) (63–65). There are four different base sites, one for each type of base in DNA.
The backbone phosphate and sugar sites are placed at the center of mass of the respective moiety.
For purine bases (adenine and guanine), the site is placed at the N1 position. For pyrimidine bases
(cytosine and thymine), the site is placed at the N3 position (63). The geometrical features of
the model are important in at least two respects. First, they offer a possibility for reverse coarse
graining or inverse mapping of the model for coupling between different length scales. The three
sites provide the necessary scaffolding to selectively reconstruct an atomistic representation on a
local level while keeping the remainder of the molecule coarse grained. Second, such features are
necessary for investigations of protein/DNA association. The ability of binding proteins to identify
the grooves is a key element in their complexation to double-stranded (ds)DNA. The proposed
model displays these motifs and facilitates studies of protein/DNA interactions that cannot be
pursued with coarser models of DNA. The details of the model and the corresponding potential
energy parameters can be found in the literature (64, 65). Here we provide a brief account of its
predictions.
Figure 2 shows melting curves for short DNA strands. Simulations are able to capture both the
width of the transition and the effect of salt concentration. The model is also able to describe the
persistence length of DNA and its dependency on ionic strength. In this regard, it is of interest to
mention that the development of the model was largely enabled by the use of efficient Monte Carlo
simulation algorithms developed over the past decade, in particular, the use of expanded ensemble
(66–68) and density-of-states ideas (69, 70), parallel tempering (71–76), and histogram reweighting
(77); without these, melting calculations would be much more computationally intensive, and the
entire parameterization of the model would have been difficult.
As alluded to above, one of the main goals of coarse-grained models is to describe the func-
tionality of DNA. Much of that functionality results from DNA’s ability to hybridize. Figure 3
shows a free energy profile as a function of the number of native contacts, which was found to be
a convenient order parameter for the calculation of melting curves (64). As seen in the figure, a
www.annualreviews.org • Coarse-Grained Simulations of Macromolecules 557

O
Phosphate
NH
O
HO P O N O
O– O Base
Sugar OH
Figure 1
Schematic representation of the 3SPN model, in which each nucleotide is represented by three interaction
sites corresponding to the phosphate, the base, and the sugar.
relatively large free energy arises when two single-stranded molecules form two native contacts;
as more contacts form, the free energy decreases steadily until the molecule is fully hybridized. Al-
though the order parameter for Figure 3 is not a true reaction coordinate, the results do suggest
that hybridization is an activated process. More recent calculations, using transition path sam-
pling simulations (78), have revealed an intriguing picture of the actual process of hybridization
with the simple coarse-grained model shown in Figure 1 (79). Figure 4 shows the probability of
forming distinct contacts between specific bases belonging to the two strands of a 30-base-pair
dsDNA molecule in the transition-state ensemble corresponding to the hybridization reaction.
The molecules do not form native contacts at the transition state but instead prefer to be offset
from the native duplex by approximately three to five nucleotides. The details of the contact map
are highly sensitive to sequence, and they depend on temperature and salt concentration. A gen-
eral feature, however, is that random sequences of DNA exhibit sharp free energy barriers toward
hybridization, reminiscent of those shown in Figure 3, whereas repetitive sequences follow a
diffusive pathway toward hybridization (79).
For numerous applications, including genomic analysis or colloidal assembly (48, 80), it is
of interest to consider hybridization when one of the strands is immobilized on a surface (or a
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Simulation (20 mM)

Simulation (50 mM)
Simulation (120 mM)
1.0
Experiment (20 mM)
Experiment (50 mM)
0.8 Experiment (120 mM)
0.6
f
0.4
0.2
0.0
280 300 320 340 360

Temperature (K)
Figure 2
Melting curves for DNA oligonucleotides. The symbols represent experimental data, and the lines show
results of the 3SPN model. In the ordinate axis, f denotes the extent of denaturation of the molecule, with 0
denoting fully hybridized DNA and unity corresponding to fully dehybridized DNA.
297 K, [NaCl] 69 mM
4
βA
275 K, [NaCl] 5 mM
2
0 2 4 6 8 10 12 14
ξ
Figure 3
Free energy profile for hybridization of a 15-base-pair DNA oligonucleotide as a function of the number of
native contacts, denoted by ξ . The blue curve was calculated at 297 K and a salt concentration (NaCl) of
69 mM. The red curve was calculated at T = 275 K and a salt concentration of 5 mM.

T
C RAN30
G all nξ
G
A
C
T
T
C
A
A
G
A
G
Chain 1 T
C
T
A
G
G
T
C
T
G
G
T 0.0 0.2 0.4 0.6 0.8 1.0
C Probability
T
G
A
T C AGA C C AGA C C T AGA C T C T T GA AG T C C GA
Chain 2
Figure 4
Contact map showing the probability that distinct bonds are formed between two complementary 30-base
strands of DNA. The contact map was constructed using configurations from the transition-state ensemble
for the hybridization reaction. The color key provides a measure of probability, and the sequence of the two
strands is provided on the corresponding axis.
particle) (81). Figure 5 shows contact maps for a duplex consisting of 15 bases. In one case the
molecule is in the bulk, and in the other, one of the strands is attached to a surface. Two features
of Figure 5 are worth highlighting. First, the melting temperature of the surface-bound dsDNA
molecule is higher than that in bulk solution, by approximately 20◦ to 30◦ , depending on sequence.
Second, the contact map corresponding to the surface-bound molecule is significantly different
from that in solution. On the surface, the contacts formed at the transition state are predominantly
native contacts, and they occur primarily toward the middle of the molecules. As before, these
contact maps are particularly sensitive to temperature, sequence, and solution conditions (e.g.,
ionic strength).
The results shown in Figures 2–5 serve to illustrate that coarse-grained models, as simple
as they might still be, are beginning to enable comprehensive studies of DNA and are starting
to deliver fundamental insights into its behavior that have been lacking. There is considerable
room for improvement, however, and to the extent that models are refined and tested, they might
contribute significantly to emerging, DNA-based technologies. One of the shortcomings of the
model outlined in Figure 1 is that base-stacking interactions are represented with a Go-like
potential (82). For predictions of new, tailor-made structures of DNA, it would be important to
remove such a constraint and include the planar geometry of the bases. Recent efforts in that
direction are promising. In a new model, based on the 3SPN approach, the spherically symmetric
base site is replaced by a rigid-body ellipsoid (83). The model can predict a number of structural
features of dsDNA without the need for potentials that bias the structure in the direction of
B-DNA, but it is unclear whether it can predict melting temperatures and rehybridization. In a
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A a A b
T T
C C
A A
A A
T T
T T
A A
C C
A A
A A
T T
C 0.0 0.2 0.4 0.6 0.8 1.0 C
A Probability A
T T
A T G A T T G T A A T T G A T A T G A T T G T A A T T G A T
Figure 5
Contact maps showing the probability that distinct bonds are formed between two complementary 15-base
strands of DNA. The contact map was constructed using configurations from the transition-state ensemble
for the hybridization reaction. The color key is the same as that used in Figure 4. The results in panel a
correspond to a situation in which the strand on the abscissa was attached to the surface at the blue site, T.
The results in panel b are for the same molecule under the same conditions, but in free solution.
different model, also based on the 3SPN platform, the number of interaction sites is expanded
from three to six, thereby providing a more complete geometrical representation of the bases
(84). It is able to describe the structure of DNA, and preliminary melting temperature predictions
have been reported to be in qualitative agreement with experiment. Such expanded models are
more computationally demanding, and the issue now is to determine whether they can predict the
structure of other forms of DNA, beyond B-DNA, and whether they can be further developed to
describe related molecules, in particular RNA. Another shortcoming of 3SPN and most existing
models based on the same platform is that electrostatic interactions are treated at the Debye-
Huckel level. For numerous situations, it is of interest to determine the role of specific counterions,
and extensions that replace the Debye-Huckel form with explicit ions would be useful. Recent work
has sought to modify 3SPN by including explicit counterions in studies of particle dimerization
(85); additional efforts in that direction are needed.
Future coarse-grained developments should also consider DNA-protein interactions, and the
delicate issues that arise vis-à-vis electrostatic effects in such systems. Recent efforts in that di-
rection are promising (49, 86–88) and suggest that coarse-grained models will be useful, if not
essential, in interpreting emerging experimental data in the biological literature.
COARSE-GRAINED MODELS OF POLYMERIC NANOCOMPOSITES

The central idea of nanocomposites is that, through the addition of a relatively small amount
of nanoparticles, it is possible to improve significantly the properties of a polymer melt. One of
the central challenges of nanocomposite research has been that of dispersing the nanoparticles
in the polymeric matrix (89). It is known that the aggregation state of the particles in the matrix
plays a key role in the behavior of the material; it is now appreciated that the performance of a
nanocomposite depends on whether the particles are uniformly dispersed (90–92). In some cases,
for example, mechanical strength can be increased by particles that aggregate to form higher-level
structures (92). Other properties, such as electrical conductivity, require that particles be dispersed

effectively in order to form percolating structures at low loadings (91). With the emergence of
better processing methods to achieve particle dispersion or aggregation within a polymer matrix
(89, 92), one of the central questions that arises is how the particle’s spatial distribution influences
a nanocomposite’s properties.
With the recent development of new experimental protocols, it is becoming possible to create
materials that exhibit remarkable properties. The challenge for theory and simulation is to de-
velop models capable of describing the structure and properties of such materials—such models
are necessary to interpret experimental data and to formulate a theory of nanocomposite behavior.
Only recently has a molecular theory of composites begun to emerge (93); some of the central
contributions of that theory have been to gradually provide a view of the structure and phase be-
havior of composites (94–97) that is comprehensive enough to explain a wide range of experimental
observations. Note, however, that recent theoretical progress based on integral equation, density
functional, and self-consistent mean field methods has been largely limited to equilibrium, and not
dynamics. A molecular theory for nanocomposites under deformation remains to be developed.

Simulations could fill an important gap in our understanding of polymer nanocomposites by
providing a molecular view of nanoparticle distribution, of macromolecular conformations around
the particles, and of the entanglement network that arises in such materials and by providing
insights into their mechanical or rheological response under deformation. A recent review has
discussed past efforts in simulating nanocomposites at the atomistic, mesoscale, and continuum
levels (20). On the one hand, given that the typical size of a nanoparticle is in the range of 5 to
100 nm, atomistic simulations have mainly focused on studies of the organization of molecules in
the immediate vicinity of the particles; several recent examples can be found in References 98–105.
Continuum studies, on the other hand, have focused on the mechanical behavior of the composites
but have not addressed the polymeric, molecular nature of the underlying materials (20). Hybrid
approaches that combine atomistic modeling and continuum methods have been limited, but offer
significant promise in nanocomposite research, particularly with regard to mechanical property
prediction (106). Attempts to describe the structure and properties of nanocomposites solely on
the basis of atomistic simulations face considerable challenges with regard to the size of the system
that can be investigated (107), and in order to describe their intermediate-to-long length scale
structure, one must adopt coarse-grained representations. As mentioned above, the challenge in
this area is not as much developing such representations, as it is developing algorithms capable of
simulating them.
Coarse-grained simulations of polymeric nanocomposites have generally resorted to lattice
models (108, 109) or to bead-spring models (107, 110–117), in which individual beads correspond
to a Kuhn segment of the polymer. In the latter case the particles are represented by spheres or
collections of spherical interaction sites connected by springs. The majority of the simulations
available in the literature have considered relatively short, unentangled molecules (108–112, 116).
Many of the unusual properties of nanocomposites, however, arise from such entanglements, and,
as alluded to above, it is therefore of interest to determine if and how nanoparticles influence the
entanglement network of a composite (118).
Only recently have combinations of molecular dynamics and Monte Carlo simulations been
able to examine the structure and elastic properties of entangled polymer composites (113, 119),
both at rest and under deformation. Advanced Monte Carlo moves, including connectivity-altering
techniques (120, 121), have been essential to ensure that the conformations of the polymers
around the nanoparticles are sampled correctly, thereby providing a faithful representation of
the entanglement network that arises in model systems. Some representative results are shown in
Figure 6 for the strain as a function of time under constant tensile and compressive stresses.
Simulations have shown that, for well-dispersed particles, the elastic moduli of the composite are
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0.8
Pure
0.6
0.4 Nanocomposite
Strain
0.2
0 Nanocomposite
–0.2
Pure
–0.4
0 2,000 4,000 6,000 8,000

Time
Figure 6
Strain as a function of time for constant-stress deformation of a model nanocomposite polymeric material.
The chains comprise 500 monomers, and the volume fraction of particles is 15%. The diameter of the
particles is five times that of the polymer monomer. The upper curves show results under tension, whereas
the bottom ones show result under compression. The results in blue correspond to deformation of the
material without nanoparticles, and those in red correspond to the nanocomposite.
higher than those of the corresponding pure polymer matrix. Consistent with experiment, simu-
lations under deformation have shown that the toughening modulus increases with the addition of
nanoparticles. Some of the central findings of this more recent work on entangled nanocomposites
have been that well-dispersed nanoparticles serve as entanglement attractors or traps. Figure 7
shows an image of the primitive path (122–127) that long polymeric molecules follow in a compos-
ite melt; one can see that long polymers wrap around the particles, thereby increasing the number
of entanglements in the nanocomposite. Furthermore, as the material is deformed, e.g., under
a b
Figure 7
Primitive path followed by polymer molecules in the vicinity of a nanoparticle dispersed in a polymer melt.
(a) A nanocomposite at equilibrium. (b) The same nanoparticle after a tensile deformation of the material, at
constant stress, and a strain of 0.5.

elongation or under compression, new entanglements are formed around the nanoparticle (119).
Such an increased number of entanglements leads to significantly different mechanical and rheo-
logical properties, including a higher plateau modulus (119, 128). Recent studies have also found
that particle size and shape can increase the number of entanglements considerably, thereby lead-
ing to composite materials with considerably different rheological properties, particularly under
deformation (107, 111, 115, 129).
Other important issues in nanocomposite research are to understand how nanoparticles are
distributed throughout the material and, perhaps more importantly, to use that understanding
to manipulate and control their positioning. Block copolymer materials have been particularly
instructive in that regard (130–136). Indeed, with an inherent structural inhomogeneity having
characteristic dimensions in the 5- to 100-nm range, they provide an ideal platform in which to
explore and further our understanding of composites. Theoretical work has been limited (137–
139), and simulations of nanoparticles in block copolymers have been scarce. Early simulations
employed lattice models to examine how dilute nanoparticles distribute themselves in a copolymer
(109, 137). Although such calculations were useful in helping to explain a number of experimental
features, including the preference of nanoparticles for interfacial or bulk regions, depending on
the nature of chemical interactions and size, they were limited to small systems. Furthermore,
by virtue of the underlying lattice, the geometrical shape of the particles was generally cubic
based. More recently, new approaches based on well-defined theoretical formalisms have enabled
coarse-grained simulations over extended regions of space. In one approach, based on a field-
theoretic description of the fluid in which particles are treated explicitly in the fields created by
the copolymer molecules (140), the particle coordinates and chemical potential field variables are
simultaneously updated, and the calculations amount to conducting Brownian dynamics simula-
tions of the particles in an implicit solvent (whose local composition is dictated by the copolymer).
Simulations using this approach have so far been performed on a lamellar phase of a copolymer, in
two dimensions; the results have been shown to be in good agreement with experiments conducted
on polystyrene-functionalized gold nanoparticles in a polystyrene-polyvinylprirrolidone diblock
copolymer melt.
In an approach similar in spirit but different in implementation, simulations of the copolymer
and the particles are conducted explicitly, but the interactions between copolymer molecules and
the particles and the copolymer are given by a coarse-grained Hamiltonian akin to that used
in field-theoretic simulations (5, 141) (or in self-consistent field theory). In other words, the
coarse-grained interactions between particles are informed by an underlying theoretical model,
thereby reducing considerably the computational requirements and avoiding the need to evaluate
pair interactions. Theoretically informed simulations of nanoparticles in copolymers have been
performed on both bulk copolymers (141) and on thin films of copolymers (132, 142), in three
dimensions. The results of such simulations also have been shown to be in good agreement with
experiment.
A particularly interesting system, which serves to illustrate the value of using block copolymers
to further our understanding of nanoparticle-polymer interactions, is described schematically in
Figure 8. In that system, a block copolymer thin film is deposited on a patterned substrate. The
role of the pattern is to control the morphology of the copolymer thin film. In the example shown
in Figure 8, which is concerned with lamellae, the pattern on the surface can stretch or compress
individual domains of the copolymer, thereby inducing pronounced conformational changes of
the molecules. When nanoparticles are added to the thin films, they serve as probes of copolymer
structure and exhibit a distinct preference for certain regions of the material. As the copolymer
morphology is perturbed by the underlying substrate pattern, the particles adopt different arrange-
ments, sometimes forming a single row, two parallel rows, or aggregates that can be visualized in
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a L0
b
0% 20% 40% φhom
Ls = L0
Ls > L0
200 nm
Stretching
LS
Figure 8
(a) Schematic representation of a copolymer thin film deposited on a stripe-patterned substrate.

Nanoparticles ( green) are preferentially dispersed in the pink domains of the diblock. The pink block
exhibits a preference for the pink regions of the substrate, and the blue blocks exhibit a preference for the
blue stripes. (b) Scanning electron micrographs of cadmium-selenide nanoparticles after dispersion in
poly-methyl-methacrylate-polystyrene diblock copolymer thin films. Results are shown for different values
of Ls and different homopolymer concentrations.
scanning electron micrographs. Figure 9 shows results of experiments and theoretically informed
simulations of small cadmium-selenide nanoparticles (5 nm in diameter), treated in such a way as to
exhibit a preference for polystyrene, dispersed in a poly-methyl-methacrylate-polystyrene diblock
copolymer thin film. As seen in the figure, the agreement between simulation and experiment is
good, particularly when one considers the relatively coarse nature of the theory.
Theoretically informed simulations of nanocomposites continue to face challenges and could
be improved in a number of respects. In the hard-particle limit (142), it is currently computa-
tionally demanding to simulate large particles and large-particle volume fractions. That problem
could be alleviated by developing new Monte Carlo moves to facilitate trial particle displacements
while lowering rejection rates. Perhaps more importantly, it is of considerable importance now to
develop approaches that will enable studies of deformation and dynamics of nanocomposites, in
the entangled regime, within the framework of theoretically informed or field-theoretic simulation
approaches.
CONCLUSIONS
A striking feature of the results shown in Figures 8 and 9 concerns the length scales that can now be
probed by simulations and experiments. We have entered an age in which molecular simulations of
relatively complex materials are feasible over large domains, encompassing the molecular details
of a macromolecule’s conformation and the broad features of structures or morphologies that
arise over micrometer regions. Experiments can now manipulate and probe matter at those length
scales, thereby enabling direct comparisons to models, and a more refined and direct interpretation
of observed phenomena in terms of well-defined molecular characteristics and processes.
This feature, which in this review has been highlighted in the context of our own experience
with block copolymer directed assembly, is not limited to this class of materials. Multiple areas

0% 20% 40% φhom
0.10
Simulation φ(x) 0.05

0.10
Experiment φ(x)
0.05
–20 –10 0 10 20 –20 –10 0 10 20 –20 –10 0 10 20

x (nm)
Figure 9
Particle concentration profiles as a function of position from simulations (top panels) and from experiments
(lower panels; see Figure 8). Different lines represent different degrees of mismatch (or stretching) between
the characteristic dimensions of the substrate pattern (Ls ) and the characteristic period of the block
copolymer in the bulk (L0 ). The black line corresponds to Ls = L0 , the blue line to Ls = 1.1L0 , and the
green line to Ls = 1.2L0 .
of soft matter, ranging from colloidal systems to protein extension, have highlighted the synergy
between concurrent experimental measurements and coarse-grained simulations. A decade of
single-molecule experiments (143, 144) and coarse-grained simulations with DNA, for example,
has benefited tremendously from the direct observation of molecular features coupled to coarse-
grained simulations (36, 145, 146).
With this increased ability to interrogate matter at nanometer length scales, new opportunities
will arise to further our understanding of macromolecular materials. Simulations of appropriately
coarse-grained models will be particularly important for the interpretation of experimental data.
Two areas of macromolecular simulation that, in spite of important efforts, continue to be in
need of additional developments involve the structure and dynamics of DNA complexes and the
deformation and dynamics of nanocomposites.
As mentioned above, DNA is increasingly used in the form of linkers to form intricate, higher-
order structures. An elementary unit of such structures often consists of a particle to which single
strands of DNA are attached. The pathways through which two DNA functionalized nanoparticles
hybridize, for example, are not fully understood. Multiscale simulations using some of the models
introduced in this review could shed considerable light onto such processes.
566 de Pablo
In chromatin, for example, a single molecule is wrapped around thousands of histones in a tight
complex whose structure continues to be a source of much debate. As it folds around these proteins
(87), DNA might partially melt and do so according to local sequence, concentration, and other
factors. Unraveling that structure and the dynamics of the packaging process will require that the
approaches described in this review be tested and expanded within the context of DNA-protein
interactions. Work of this nature might also require that one resorts to hierarchical approaches,
in which different levels of description communicate with each other and are used to address
systematically longer or shorter length scales in a concerted manner.
Going beyond DNA to RNA, which exhibits a rich variety of folded structures (152), it will
be important to develop models that do not have some of the site-specific restrictions of existing
mesoscale models of DNA. As mentioned above, recent attempts to remove such restrictions
in the context of DNA are promising (84), but the resulting models are more computationally
demanding and need to be further explored and extended to address the challenges that arise in
RNA research. This is a fertile area of research in which multiscale simulations have the potential
to make major contributions.
Within the realm of nanocomposites, equilibrium simulations have been largely limited to small
particle sizes and relatively low particle volume fractions. As mentioned above, key challenges are
to simulate large systems (so that many large particles can be incorporated into a sample) and to
develop algorithms that allow one to sample configuration space through major displacements of
relatively large particles in a sea of other particles and long polymeric molecules. Recent algorithms
such as the bijective mapping approach of Uhlherr & Theodorou (153), coupled to the coarse-
graining strategies discussed in the context of theoretically informed techniques, offer promise
on that front. Clearly, simulations that overcome such limitations and that manage to identify
correlations between measurable properties and particle characteristics and organization would
be particularly useful.
In the case of dynamic or nonequilibrium properties, it is important to point out that me-
chanical or rheological experimental data are generated under conditions that are not accessible
to conventional simulations. Relevant experimental timescales and length scales in a rheometer
are orders of magnitude longer than those probed by simulations of many-particle systems in
nanometer-length-scale simulation boxes. In order to sample longer, relevant scales, simulations
and models aiming to reproduce and interpret such data must deal with the issue of entanglements,
their characteristics, and how these are related to the material’s response under stress. Recent work
with pure polymers suggests that the concept of slip links (147–150) might be particularly useful in
this regard, particularly if coupled to a real-space representation of the molecules (151), as is done
in theoretically informed simulations. Future simulations that incorporate such concepts, partic-
ularly in the context of structured polymers and nanocomposites, would help address a number of
longstanding questions in the general area of nanocomposite rheology and processing.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
The author is grateful for support from the National Science Foundation and the Semiconductor
Research Corporation. The author is also grateful to the European Community for a Marie Curie

Fellowship and to Prof. Manuel Laso for helpful discussions and his hospitality during a sabbatical
stay at the Universidad Politecnica de Madrid.
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PC62FrontMatter ARI 18 February 2011 17:56
Annual Review of
Physical Chemistry
Volume 62, 2011

Contents
Laboring in the Vineyard of Physical Chemistry

Benjamin Widom p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
The Ultrafast Pathway of Photon-Induced Electrocyclic

Ring-Opening Reactions: The Case of 1,3-Cyclohexadiene
Sanghamitra Deb and Peter M. Weber p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19
Coarse-Grained (Multiscale) Simulations in Studies of Biophysical

and Chemical Systems
Shina C.L. Kamerlin, Spyridon Vicatos, Anatoly Dryga, and Arieh Warshel p p p p p p p p p p p p41
Dynamics of Nanoconfined Supercooled Liquids
R. Richert p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65
Ionic Liquids: Structure and Photochemical Reactions
Edward W. Castner Jr., Claudio J. Margulis, Mark Maroncelli,
and James F. Wishart p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p85
Theoretical Study of Negative Molecular Ions
Jack Simons p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Theoretical and Computational Protein Design
Ilan Samish, Christopher M. MacDermaid, Jose Manuel Perez-Aguilar,
and Jeffery G. Saven p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129
Melting and Freezing of Metal Clusters
Andrés Aguado and Martin F. Jarrold p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 151
Astronomical Chemistry
William Klemperer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 173
Simulating Chemistry Using Quantum Computers
Ivan Kassal, James D. Whitfield, Alejandro Perdomo-Ortiz, Man-Hong Yung,
and Alán Aspuru-Guzik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
Multiresonant Coherent Multidimensional Spectroscopy
John C. Wright p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209
Probing Free-Energy Surfaces with Differential Scanning Calorimetry
Jose M. Sanchez-Ruiz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 231
viii
Role of Solvation Effects in Protein Denaturation: From

Thermodynamics to Single Molecules and Back
Jeremy L. England and Gilad Haran p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 257
Solid-State NMR Studies of Amyloid Fibril Structure
Robert Tycko p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
Cooperativity, Local-Nonlocal Coupling, and Nonnative Interactions:
Principles of Protein Folding from Coarse-Grained Models
Hue Sun Chan, Zhuqing Zhang, Stefan Wallin, and Zhirong Liu p p p p p p p p p p p p p p p p p p p p p 301
Hydrated Acid Clusters
Kenneth R. Leopold p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 327
Developments in Laboratory Studies of Gas-Phase Reactions for

Atmospheric Chemistry with Applications to Isoprene Oxidation
and Carbonyl Chemistry
Paul W. Seakins and Mark A. Blitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 351
Bonding in Beryllium Clusters

Michael C. Heaven, Jeremy M. Merritt, and Vladimir E. Bondybey p p p p p p p p p p p p p p p p p p p 375
Reorientation and Allied Dynamics in Water and Aqueous Solutions
Damien Laage, Guillaume Stirnemann, Fabio Sterpone, Rossend Rey,
and James T. Hynes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 395
Detecting Nanodomains in Living Cell Membrane by Fluorescence
Correlation Spectroscopy
Hai-Tao He and Didier Marguet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Toward a Molecular Theory of Early and Late Events in Monomer
to Amyloid Fibril Formation
John E. Straub and D. Thirumalai p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 437
The Density Matrix Renormalization Group in Quantum Chemistry
Garnet Kin-Lic Chan and Sandeep Sharma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
Thermodynamics and Mechanics of Membrane Curvature Generation
and Sensing by Proteins and Lipids
Tobias Baumgart, Benjamin R. Capraro, Chen Zhu, and Sovan L. Das p p p p p p p p p p p p p p p 483
Coherent Nonlinear Optical Imaging: Beyond Fluorescence
Microscopy
Wei Min, Christian W. Freudiger, Sijia Lu, and X. Sunney Xie p p p p p p p p p p p p p p p p p p p p p p p 507
Roaming Radicals
Joel M. Bowman and Benjamin C. Shepler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 531
Coarse-Grained Simulations of Macromolecules:
From DNA to Nanocomposites
Juan J. de Pablo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 555
Contents ix
New Developments in the Physical Chemistry of Shock Compression

Dana D. Dlott p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 575
Solvation Dynamics and Proton Transfer in Nanoconfined Liquids
Ward H. Thompson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 599
Nonadiabatic Events and Conical Intersections
Spiridoula Matsika and Pascal Krause p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 621
Lessons in Fluctuation Correlation Spectroscopy
Michelle A. Digman and Enrico Gratton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 645
Indexes
Cumulative Index of Contributing Authors, Volumes 58–62 p p p p p p p p p p p p p p p p p p p p p p p p p p p 669

Cumulative Index of Chapter Titles, Volumes 58–62 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 672
Errata
An online log of corrections to Annual Review of Physical Chemistry articles may be

found at http://physchem.annualreviews.org/errata.shtml
x Contents

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PC62CH26-de-Pablo ARI 25 February 2011 16:25

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Annu. Rev. Phys. Chem. 2011. 62:555–74 Keywords

The Annual Review of Physical Chemistry is online at Abstract

to provide readers with a starting point for further studies.

COARSE-GRAINED MODELS OF DNA

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Simulation (20 mM)

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COARSE-GRAINED MODELS OF POLYMERIC NANOCOMPOSITES

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dynamics. A molecular theory for nanocomposites under deformation remains to be developed.

0 2,000 4,000 6,000 8,000

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(a) Schematic representation of a copolymer thin ﬁlm deposited on a stripe-patterned substrate.

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0% 20% 40% φhom

Simulation φ(x) 0.05

–20 –10 0 10 20 –20 –10 0 10 20 –20 –10 0 10 20

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methods, and emerging applications. MRS Bull. 32:905–11

micromechanics: an overview. Philos. Mag. 83:3475–528

dynamics. Curr. Opin. Struct. Biol. 18:185–93

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DNA-hybrid dimer structures: experimental characterization and coarse-grained molecular dynamics

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posite and its impact on rheology. J. Chem. Phys. 119:1777–88

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Volume 62, 2011

Laboring in the Vineyard of Physical Chemistry

The Ultrafast Pathway of Photon-Induced Electrocyclic

Coarse-Grained (Multiscale) Simulations in Studies of Biophysical

Role of Solvation Effects in Protein Denaturation: From

Developments in Laboratory Studies of Gas-Phase Reactions for

Bonding in Beryllium Clusters

New Developments in the Physical Chemistry of Shock Compression

Cumulative Index of Contributing Authors, Volumes 58–62 p p p p p p p p p p p p p p p p p p p p p p p p p p p 669

An online log of corrections to Annual Review of Physical Chemistry articles may be

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