Simulation of Biomolecules

1. Force fields: Energy terms, Topology and parameter files

Simulation of Biomolecules – p. 1

Simulation of Biomolecules
1. Force fields: Energy terms, Topology and parameter files 2. Molecular Dynamics - Preceding Information: Computation of nonbonded interactions, Introduction to Statistical Mechanics

Simulation of Biomolecules – p. 1

Simulation of Biomolecules
1. Force fields: Energy terms, Topology and parameter files 2. Molecular Dynamics - Preceding Information: Computation of nonbonded interactions, Introduction to Statistical Mechanics 3. Molecular Dynamics I: The Idea, Integrating the equations of motion, MD in various ensembles, Thermostats

Simulation of Biomolecules – p. 1

Simulation of Biomolecules
1. Force fields: Energy terms, Topology and parameter files 2. Molecular Dynamics - Preceding Information: Computation of nonbonded interactions, Introduction to Statistical Mechanics 3. Molecular Dynamics I: The Idea, Integrating the equations of motion, MD in various ensembles, Thermostats 4. Molecular Dynamics II: Langevin dynamics, Brownian dynamics

Simulation of Biomolecules – p. 1

Simulation of Biomolecules
1. Force fields: Energy terms, Topology and parameter files 2. Molecular Dynamics - Preceding Information: Computation of nonbonded interactions, Introduction to Statistical Mechanics 3. Molecular Dynamics I: The Idea, Integrating the equations of motion, MD in various ensembles, Thermostats 4. Molecular Dynamics II: Langevin dynamics, Brownian dynamics 5. Monte Carlo Simulations: The Idea: Importance Sampling and the Metropolis Method, Trial Moves, Monte Carlo simulations in various ensembles

Simulation of Biomolecules – p. 1

MD in various ensembles. Advanced sampling techniques: Biased potential techniques. Force fields: Energy terms. Introduction to Statistical Mechanics 3. Energy landscape paving and metadynamics. Thermostats 4. Molecular Dynamics I: The Idea.Simulation of Biomolecules 1. Brownian dynamics 5. Integrating the equations of motion. Monte Carlo simulations in various ensembles 6. Molecular Dynamics II: Langevin dynamics. Trial Moves. Molecular Dynamics .Preceding Information: Computation of nonbonded interactions. 1 . Monte Carlo Simulations: The Idea: Importance Sampling and the Metropolis Method. Parallel tempering / replica exchange MD Simulation of Biomolecules – p. Topology and parameter files 2.

2 .Simulation of Biomolecules Force fields: • Energy terms in all-atom force fields • Non-covalent interactions • Parameterization of force fields • Topology and parameter files • Coarse-grained force fields • Knowledge-based force fields Simulation of Biomolecules – p.

N − 2 bond angles (involving 2 bonds). 3 .All-atom force fields • classical biomolecular simulations: approximation to quantum dynamics • classical force fields parameterized based on quantum-chemical simulations • the potential (≡ force field) is a function of the coordinates of all particles (N atoms) • energy expressed in terms of atom pairs. N − 3 torsion angles (between 3 bonds) • together with 6 degrees of freedom (DOF) for overall translation and rotation: 3N DOFs Simulation of Biomolecules – p. triples and quadruples using the concept of chemical bonding: N − 1 bond lengths.

• Nonbonded interactions arise from electrostatic and van der Waals interactions. rc ) + (1) • Higher order terms arise from. rb .All-atom force fields • the potential can be expressed as U= a U (1) (ra ) + ab U (2) (ra . e. and so on. rd ) + . • Bonded contributions arsise from bond vibrations. rb . abcd + abc U (3) (ra . bond angle bending and torsion around bonds. . Simulation of Biomolecules – p. • An alternative expression to Eq.. .g. rc . Thus. rb ) U (4) (ra . (1) is the division of U into bonded and nonbonded contributions. The latter interact with the former. polarisation where multipoles induce other multipoles. 4 . the problem can only be solved iteratively.

5 . • All nonbonded interactions are added up: Simulation of Biomolecules – p.All-atom force fields • Nonbonded interactions are calculated between the atoms from different molecules and for atoms of the same molecule if they are separated by more than thre bonds.

Two-body potentials • Pairwise interactions are functions of the distance between two atoms a and b: rab = |ra − rb | • Simple pairwise interactions: Simulation of Biomolecules – p. 6 .

the so-called London or dispersion interactions.6 1. • The 6/12 Lennard-Jones (LJ) potential for the van der Waals interactions is a compromise between accuracy and computational efficiency. 7 .Two-body potentials: Lennard-Jones potential (2) ULJ vdW rij = Um  r  12 −2 vdW rij r 6   Um 0.4 1.8 2 distance (A) • The attractive r−6 term originates from quantum mechanics due to electron correlation. • The repulsive r−12 term has a quantum origin in the interaction of the electron clouds with each other (Pauli exclusion) plus internuclear repulsions.8 1 1. Simulation of Biomolecules – p.2 1.

6 1.Two-body potentials: Lennard-Jones potential (2) ULJ vdW rij = Um  r  12 −2 vdW rij r 6   Um 0. in the outer electron shells: U∝ αi αj αi /Ni∗ + ∗ αj /Nj Simulation of Biomolecules – p.8 1 1. 8 .2 1. (2) vdW • At r = rij the LJ potential has its minimum with ULJ = Um . and number of electrons. ULJ → 0: short range van der Waals (vdW) force. α.4 1.8 2 distance (A) (2) • For r → ∞. vdW vdW vdW • rij = ri + rj : sum of the vdW radii of atoms i and j. N ∗ . • The potential depth is determined by the polarisabilities.

Simulation of Biomolecules – p.H 0 −1000 −2000 0 0.3 0. • The dielectric constant ǫ describes the screening of the electrostatic interactions by a polarizable environment: ǫ = 1 for vacuum.4 0. attractive for opposite charges. ǫ = 4 for the interior of a protein..1 0.. • Repulsive if particles have the same charge. ǫ = 80 for water.C O.. 9 .Two-body potentials: Coulomb potential 2000 (2) Ucoul qi qj = Kcoul ǫr energy (kcal/mol) 1000 C.5 distance (A) • For ionic interactions between fully or partially charged groups..2 0.

carried by a proton). • The Coulomb potential constant is given by Kcoul = 1/(4πǫ0 ).0221 × 1023 /4184 kcal mol−1 follows: Kcoul 1J m kcal = ≈ 332 · 4π(8. 10 . 1 C = 1/(1.6022 × 10−19 ) esu (esu is the electrostatic charge unit for the elementary charge.Two-body potentials: Coulomb potential Ucoul = Kcoul (2) qi qj ǫr • Unlike vdW interactions. where the permittivity of a vacuum is ǫ0 = 8. • With 1 m = 1010 Å. the Coulomb interactions decay slowly with distance.8542 × 10−12 )C2 mol esu2 Simulation of Biomolecules – p.8542 × 10−12 C2 m−1 J−1 . and 1 J ≡ 6. e0 .

1. • An electric dipole consists of two charges q and −q separated by a distance l. 11 . • All heteronuclear two-atomic molecules are polar due to the difference of electronegativity of both atoms results in partial charges (e.08 D in HCl). but a dipole can be induced by an external electric field.208 e0 Å.. The dipole is represented by a vector µ. which points from the negative to the positive charge.Electrostatic interactions in molecules • Most interactions in molecules are electrostatic.g. Dipole moment unit: 1 Debye = 1 D = 0.g. • Depending on the symmetry. −q• → •q. • In an external field the dominant molecular multipole is the dipole. • Apolar molecules do not have a permanent electric dipole moment. 1. Simulation of Biomolecules – p..85 D in H2 O). a multiatom molecule can be polar (e.

12 .5 −0.1 Type of interaction monopole-monopole monopole-dipole dipole-dipole London (vdW) Distance dependence 1/r 1/r2 1/r3 1/r6 Examples in proteins salt bridges Lys-ammonium and α-helix dipole backbone C=O in α-helix all atoms Simulation of Biomolecules – p.5 −0.Electrostatic interactions in molecules Permanent and induced dipole moments are important in biochemistry: Typical energy values [kcal/mol] −50 to 5 −3.

• The hydrogen bond energy depends on the geometry of D. 13 . O and F. Simulation of Biomolecules – p. H. A and AA elements and the hybridization state.Hydrogen bonds • Hydrogen bonds derive from electrostatic interactions between the positive partial charge of a H atom bound to an electron-withdrawing ‘donor’ (D) and the lone pair of electrons at the ‘acceptor’ atom (A): δ− D − Hδ+ · · ·δ− A where D. and A.A = N. The optimal D − H · · · A angle is 180◦ . • The optimal H · · · A − AA angle (AA = anterior acceptor) depends on the D.

1 3.1 2.7±0.1 Type amide-carbonyl hydroxyl-carbonyl hydroxyl-hydroxyl amide-hydroxyl amide-imidazole ammonium-carboxyl guanidinium-carboxyl >N−H· · · O=C< −O−H· · · O=C< −O−H· · · O−H >N−H· · · O−H >N−H· · · N≤ −NH+ · · ·− OOC− 3 . Thr. Tyr His ˘¸ LysâAS-Asp ˘¸ ArgâAS-Asp Simulation of Biomolecules – p. 14 . Tyr Ser.Hydrogen bonds Hydrogen bonds in proteins: D· · · A distance [Å ] 2.2 2.1 2.. Thr.8±0. Thr.9±0.8±0. −NH+ · · ·− OOC− 2 Example backbone Ser. Tyr Ser.7±0.1 2..1±0.9±0.1 2.

d2 r F (r) = −kvib (r − r0 ) = m 2 . m is replaced by the reduced mass µ = (m1 m2 )/(m1 + m2 ) Simulation of Biomolecules – p. • The harmonic potential using Hooke’s law is the simplest molecular-mechanics formulation for bond vibration.Two-body potentials: Bond length potentials • Bond length potentials model small-scale deviations about the equilibrium bond length r0 . r − r0 . 15 . dt kvib = mω 2 . d2 r/dt2 . and the acceleration. • For atomic pairs of different species with masses m1 and m2 . (2) • From the angular frequency ω (number of radians per unit time). the force constant kvib can be calculated for a particular bond vibration using experimental or quantum mechanical data. and the mass m. which is connected to the wavelength via λ = 2πc/ω. • According to Hooke’s law. the force F is proportional to the displacement.

given by the Morse potential. (2) Simulation of Biomolecules – p. for instance.Two-body potentials: Bond length potentials • From (2) the bond length potential follows: bond potential UHO (2) kvib (r − r0 )2 = 2 harmonic potential Morse potential (3) r0 bond length where the subscript HO is for harmonic oscillator. UHO a good description for bond vibration. • More realistic functions for bond vibration is. • But since kvib usually large and and bond lengths often fixed in biomolecular simulations. 16 .

. In propane. rc ) = arccos(e1 · e2 ) with the unit vectors along the bonds: Simulation of Biomolecules – p.5◦ and C–C–H ≈ 109. 17 .5◦ .g.5◦ • Exact orbits only exist if all bonded atoms are of the same type. e.g. e. the H–C–H bond angles ≈ 107.. for instance. • Electron lone pairs influence the geometry too. the C–C–C bond angle is ≈ 112. as in methane.5◦ . • The bond angle is determined by θ ≡ θ(ra . rb . ◦ sp hybridization → linear geometry with θ ≈ 180◦ ◦ sp2 hybridization → trigonal planar with θ ≈ 120◦ ◦ sp3 hybridization → tetrahedral with θ ≈ 109.Three-body potentials: Bond angle potentials • Bond angle arrangement around each atom in a molecule is governed by the hybridization stage of this atom.

(3) Simulation of Biomolecules – p. 18 . • It avoids the calculation of inverse trigonometric functions and singularity problems for linear bond angles. |rb − ra | e2 = rc − ra |rc − ra | • The bond angle potential is often expressed as a harmonic function in terms of angle cosines: UHO (θ) = kbend (cos θ − cos θ0 )2 • Advantage of this trigonometric potential is its boundedness and its ease of implementation and differentiation.Three-body potentials: Bond angle potentials e1 = rb − ra .

Simulation of Biomolecules – p. trans or staggered state). and lowest when they are optimally separated (anti. 19 . in ethane the torsional strain is highest when the two methyl groups are nearest (eclipsed or cis) state. • The functional form is force fields is (4) U (φ) = n Vn [1+cos (nφ − φ0 )] 2 • n is the periodicity of the rotational barrier and Vn the associated barrier height. resonance stabilization and electronic repulsions (quantum mechanical effects) • For example.Four-body potentials: Bond torsion potentials • Origin of torsional potential: relief of steric congestion.

k between them: φ ≡ φ(ra .Four-body potentials: Bond torsion potentials • Often φ0 = 0. rc . rd ) = arccos (ei × ej )(ej × ek ) sin θij sin θjk • Combination of two. a. j.and threefold symmetry to reproduce cis/trans and trans/gauche energy differences: O3 O2 4 dihedral energy [kcal/mol] 2 fold 3 fold sum O3 C3 C2 O2 cis cis O3 O2 3 U (4) V2 (φ) = [1 + cos(2φ)] 2 V3 + [1 + cos(3φ)] 2 2 trans 1 gauche 0 0 60 120 180 240 gauche 300 360 O2 O3 gauche trans dihedral angle [deg] Simulation of Biomolecules – p. 20 . b. π so that U (4) (φ) = Vn n 2 [1 ± cos nφ] • The torsional angle φ is determined by the the positions of the four atoms involved. rb . d and the three bonds i. c.

IR. and H−C−N−C Simulation of Biomolecules – p. Raman and microwave spectroscopy and/or quantum mechanical calclations for model compounds. H−C−C=0. • Examples for model compounds: ◦ hydrocarbons like ethane. C−C−O−H. ethanal and N-methyl formamide for H−C−N−H. for serine and threonine) ◦ methylamine.Four-body potentials: Bond torsion potentials • n and Vn are determined for low molecular weight compounds experimentally using NMR. propane or cyclohexane for rotations about single C−C bonds ◦ ethylbenzene for rotations about CA−C bonds in ring systems (CA is an aromatic carbon here) ◦ alcohols like methanol and propanol for H−C−O−H. 21 .g. H−C−C−O and C−C−C−O sequences (e..

g. Asp and Glu side chains ◦ C−N−N−N : for planarity of the guanidinium group in Arg ◦ various carbons and nitrogens in the side-chain rings of Phe. d. b. 22 . c. the C-terminus. for which the central atom a is bonded to b. c. Tyr and Trp Simulation of Biomolecules – p. • Examples: ◦ C−CA−N−0 : for planarity around peptide bond ◦ C−CA−O−0 : for planarity of the carboxy group in.. as the angle between the planes a − b − c and b − c − d. d. e.Four-body potentials: Improper torsion • ‘improper torsion’ is also known as ‘out-of-plane bending’ • To enforce planarity or maintain chirality about certain groups: O (4) UHO (ω) kimp 2 = ω 2 CA C O where ω is the improper angle defined for the four atoms a.

23 .Cross terms • Cross terms couple the as independent assumed contributions to the potential energy function arising from bonded interactions. • Schematic representation of various cross terms: Simulation of Biomolecules – p.

• A torsion/torsion cross term is included in CHARMM by CMAP which accounts for the interdependence of the Ramachandran angles Φ and Ψ. which is commonly used in force fields (e. a stretch/bend cross term for a bonded-atom sequence abc allows bond lengths a − b and b − c to increase/decrease as θabc decreases/increases. • Cross terms are corrections to the potential nergy function for a better agreement with the results from experiment and quantum chemical calculations.g. in CHARMM). • A variation of the stretch/bend term is the Urey-Bradley (UB) term. Simulation of Biomolecules – p. 24 .Cross terms • For example.. The UB potential is a simple harmonic function of the interatomic distance between atoms i and k in the bonded sequence ijk.

Summary: Potential energy function The total energy function for the CHARMM potential is: U= bonds kb (b − b0 )2 + angles kθ (θ − θ0 )2 + dihedrals + nonbonded pairs ij + Urey− Bradley kUB (s − s0 )2 + Vn [1 + cos (nφ − φ0 )] + kω (ω − ω0 )2 2 n impropers   12 6 vdW vdW rij rij  + Kcoul qi qj Uij  −2 r r ǫrij UCMAP (Φ. Ψ) residues Simulation of Biomolecules – p. 25 .

angles. and nonbonded interactions between all atoms not bound to each other or to a common atom. restoring "natural" values of bond lengths and angles. • More elaborate force fields may also include either Urey-Bradley terms (1. etc. potentials.W. • The atoms of a molecule may be thought of as joined together by mutually independent springs. • Steric interactions are included in the v. the sums extend over all bonds. H-bonding terms. torsions. Simulation of Biomolecules – p. 26 .3-nonbonded interactions) or cross-interaction terms.d.Summary: Potential energy function • All force fields consider a molecule as a collection of particles held together by some sort of elastic forces. • In these expressions. • All forces are defined in terms of potential energy functions of the internal coordinates of the molecules that constitute the molecular force field.

different ‘atom types’ are used for the same element. one zinc cation • The more atom types for the same chemical element. the better the experimental results can be reproduced. 27 . for instance. aromatic carbon in a phenyl ring) and hybridization. • In CHARMM22. 12 hydrogens. one heme iron. 11 nitrogens. 7 oxygens. Simulation of Biomolecules – p.g. • A reasonable assumption since bond lengths and bond angles tend to adopt similar values in different molecular species.Atom types in force fields • Transferability: The principle of transferability assumes that potentials can be developed to incorporate all experimental data for model compounds and the applied successfully to te prediction of large biological molecules composed of the same chemical subgroups. • To represent the different chemical environment (e. 3 sulfurs.. there are around 57 atom types: 21 carbons. one calcium cation.

28 .Atom types in force fields Examples of atom types defined in CHARMM: Simulation of Biomolecules – p.

29 .Atom types in force fields Examples of atom types as used in polypeptides in CHARMM: Simulation of Biomolecules – p.

0900 0.4400 *CA CB .8400 122.8400 IC N C 1.07 ! | HB1 ATOM HA HB 0.4900 IC N CA C +N 1.47 ! | ATOM HN H 0.3551 126. 30 .7700 111.09 ! O=C ATOM HB3 HA 0.5390 1.3558 116.9996 1.4592 114.0000 180.3558 1.5200 126..51 BOND CB CA N HN N CA BOND C CA C +N CA HA CB HB1 CB HB2 DOUBLE O C IMPR N -C CA HN C CA +N O CMAP -C N CA C N CA C +N DONOR HN N ACCEPTOR O C IC -C CA HN 1.31 ! HN-N ATOM CA CT1 0.4592 114. CB HB3 180.3551 126.0000 180.0000 180.09 ! | GROUP ! ATOM C C 0.00 GROUP ATOM N NH1 -0.0000 180.4400 116.4900 *N IC -C N CA C 1.5390 116.09 ! | HB3 ATOM HB2 HA 0.0000 123..2297 1.09 ! | / GROUP ! HA-CA--CB-HB2 ATOM CB CT3 -0.27 ! | \ ATOM HB1 HA 0.4400 IC +N CA O 1.4200 114.2300 115.8400 *C IC CA C +N +CA 1.5461 Simulation of Biomolecules – p.51 ATOM O O -0.Force fields: Topology file RESI ALA 0.4613 1.

ANGLES ! !V(angle) = Ktheta(Theta . S0 2..Force fields: Parameter file BONDS ! !V(bond) = Kb(b ...b0)**2 !Kb: kcal/mole/A**2 !b0: A ! !atom type Kb b0 . CT3 CT1 222..Theta0)**2 !Ktheta: kcal/mole/rad**2 !Theta0: degrees ! !V(Urey-Bradley) = Kub(S .S0)**2 !Kub: kcal/mole/A**2 (Urey-Bradley) !S0: A ! !atom types Ktheta Theta0 Kub ..10 22.500 1..500 110. 31 .. HA CT1 CT3 34.5380 .53 .17900 Simulation of Biomolecules – p..

C CT1 NH1 C 0. 32 ..4 φ : C−N−CA−C Ψ : N−CA−C−N −180 −180 φ 0 180 0 −180 −120 −60 0 60 120 180 angle [deg] Simulation of Biomolecules – p. 180 1.8 Ψ 0 !Kchi: kcal/mole !n: multiplicity !delta: degrees ! !atom types Kchi n delta .Force fields: Parameter file DIHEDRALS ! !V(dihedral) = Kchi(1 + cos(n(chi) .00 ....2 phi psi energy [kcal/mol] 0.00 NH1 C CT1 NH1 0.6000 1 0.2000 1 180.

NH1 X X H 20. psi0 0. CMAP ! 2D grid correction data. NH1 X X H includes the improper dihedral for the peptide group. 33 ..00 The X is a wildcard. psi alanine. proline and glycine dipeptide ! surfaces.e..0000 . ! alanine map C NH1 CT1 C NH1 CT1 C NH1 24 ... ... i.. The following surfaces are the correction ! to the CHARMM22 phi.psi0)**2 !Kpsi: kcal/mole/rad**2 !psi0: degrees ! !atom types Kpsi . NH1 C CT1 H. Simulation of Biomolecules – p...Force fields: Parameter file IMPROPER ! !V(improper) = Kpsi(psi .

.j/ri. Simulation of Biomolecules – p..110000 2.i.j)**12 .000000 CA -0.i + Rmin/2.j/ri. C -0.i. 34 .j)**6] !epsilon: kcal/mole..Force fields: Parameter file NONBONDED ! !V(Lennard-Jones) = Eps.i.992400 .i * eps.j = Rmin/2.i.j = sqrt(eps.j[(Rmin.2(Rmin..j) !Rmin/2: A.i. Rmin.070000 1.j ! !atom epsilon Rmin/2 . Eps.

pH. which must be interpreted and incorporated in the energy model. ◦ experimental data collected under different conditions (solvent. Unrealistic choices for one group of parameters can be compensated for by adjustment of another in order to reproduce a set of structural and energetic data. • The energy terms should have clear physical significance with parameters calibrated by empirical fitting of crystal data. 35 . Simulation of Biomolecules – p. • The combinations of parameters that can be used are endless. rotational barriers of analogous small molecules.Parameterization • Parameterization process for potential energy functions is a difficult task. • Problems arise from ◦ approximations made in the extension of data from small to large systems. vibrational frequencies and quantum-chemical data. ions).

g. use of distributed multipoles instead of atomic point charges only (polarizable force fields). • Energy parameters are not transferable from one force field to another! • Need of improvement: ◦ Determination of partial charges. 36 .Parameterization • In summary. e. ◦ Conflicting results from different force fields. Simulation of Biomolecules – p. ◦ Improvement of electrostatic potential. • Only if constructed and parameterized correctly will the energy model allow reliable structural predictions. ◦ Solvent representation and interpretation of results in the absence of solvent. much freedom and manipulation are possile in parameterizing a given energy function..

37 . ff96. lipids united-atom ff Simulation of Biomolecules – p. overstabilization of helices fixed the overstabilization of helices of ff99 reparameterized partial charges of f99. yet still biased towards helices reparameterization of nucleic acids and torsional force constants of protein backbone general Amber force field. provision for polarizability. DNA proteins. ff98 ff99 ff99SB ff03 proteins proteins. RNA. DNA proteins. RNA. RNA. RNA. DNA proteins. usually used for the ligands in protein-ligand interactions CHARMM GLYCAM sugars AMBER force fields implemented in AMBER and GROMACS CHARMM19 proteins.Overview of all-atom force fields Program Force fields Molecules Comments AMBER ff94. ff96 good due to error cancellation good nonbonded interactions. DNA any molecule bsc0 GAFF all-atom ff.

alkanes. GROMACS GROMOS96.Overview of all-atom force fields CHARMM22 proteins all-atom ff. parameterized for TIP3P. prounited-atom ff. lipids. proteins. lipid GROMOS43a2. 38 . SPC water GROMOS53a6 model GROMOS force fields implemented in GROMOS and GROMACS OPLS-UA proteins united-atom ff. sugars ff available (Berger lipids). NAMD. TIP3P and TIP4P water models OPLS-AA proteins all-atom ff. teins. can also be used with implicit solvation the CHARMM22 potential with the CMAP backbone correction based on CHARMM22/CMAP CHARMM22/CMAP proteins CHARMM27 GROMOS OPLS proteins. sugars based on OPLS-AA OPLS-2005 OPLS force fields implemented in GROMACS and NAMD Simulation of Biomolecules – p. DNA. RNA. partial charges from quantum-chemical calculations. sugars CHARMM force fields implemented in CHARMM. TIP3P and TIP4P water models OPLS-2001. no implicit solvent.

so-called beads. • For proteins one typically has 2 beads per amino acid along the backbone and.Coarse-grained force fields • Several nuclei (and electrons) are lumped into pseudo atoms. • Bonded and nonbonded interactions between beads similar to those between atoms in all-atom models. 39 . between 0 and 3 beads for the sidechain. Simulation of Biomolecules – p. depending on the amino acid.

energy functions. and that pairs of residues appear together in a particular relative geometry.g.. • The probabilities are calculated that residues appear in specific configurations (e.. 40 .g. which derive from the database of known protein structures. rotamer conformations or buried versus surface environments). and p are their relative probabilities of occurrence in the database. or statistical. Simulation of Biomolecules – p.Knowledge-based force fields • An alternative to physics-based force fields are knowledge-based. • These probabilities are converted into an effective potential energy using the Boltzmann equation ∆G = −kB T ln p(c1 . a torsion angle) of the same or a neighbouring residue. p(c1 )p(c2 ) where c1 is an amino acid type and c2 a structure descriptor (e. c2 ) .

Rosetta (David Baker) • References: S. 7. Curr. Struct. Rooman. Bahar. Opin. 3. Opin. 5. 229-235 (1995) R. Biol. Knowledge-based potential functions in protein design. Opin. Curr. Ranganathan. Comparison of database potentials and molecular mechanics force fields. Biol. 12. Curr. Curr. Moult. Biol. Generating and testing protein folds. 195-209 (1996) J.P. 194-199 (1997) W. Wodak and M.L. Struct. 6. Jernigan and I. Struct. Russ and R. Struct. 249-259 (1993) M. • Disadvantage: these energy functions are phenomenological and cannot predict new behaviour absent from the training set. Opin. 41 . Knowledge-based potentials for proteins. Struct.J. Curr.Knowledge-based force fields • Advantage: any behaviour seen in known protein structures can be modeled. Structure-derived potentials and protein simulations. Opin. • Examples: Go models. 447-452 (2002) Simulation of Biomolecules – p. Associated Memory Hamiltonian (Peter ¯ Wolynes). Sippl. even if a good physical understanding of the behaviour does not exist. Biol. Biol.

Solvation Simulation of Biomolecules – p. 42 .

Common water models are: ● ● solvent-inaccessible low high dielectric medium dielectric cavity containing for the solvent the solute Explicit solvent interactions are replaced by an energy term based on solvent's mean field behavior. Implicit Solvent Explicit solvent : Implicit solvent : ● Every water molecule is modeled explicitly. ● TIP3P TIP5P .Explicit vs. Most implicit solvent models start from a continuum electrostatic description for the solvent.

Explicit vs. But not every implicit-solvent implementation is efficient ! . Implicit Solvent Approximation ! lost information : explicit solvent Efficient ? continuum electrostatics ➢ ➢ Enormous decrease in degrees of freedom.

Assumption 1 : sum over groups i Assumption 2 : Assumption 3 : .Implicit solvent 1 : EEF1 EEF1 = Effective Energy Function W(R) for proteins with coordinates R in solution.

Implicit solvent 2 : Generalized Born models The reaction field potential can be computed by solving the Poisson-Boltzmann equation: dielectric constant of the solvent Debye-Hückel screening factor solute charge density .

JACS 112 (1990).Generalized Born models Solving the PB equation for a spherical solute with radius R. the generalized Born (GB) theory was developped. and dielectric constant gives the Born formula (Born.. which are conventionally computed within Coulomb-field approximation (CFA) : . 45) : Inspired by the Born formula. Z. Phys. The most reliable GB formula is Still's equation (Still et al. 6127) : Born radii Needs the Born radii as input. charge q. 1 (1920).

Born radii .

. 3055 Beyond Coulomb-field approximation ? in GBSW : in Gbr6 : . JCC 24 (2003). 1578 Schaefer et al. 10606 ACE Schaefer and Karplus. JCP 116 (2002). JCC 22 (2001)..Calculation of Born radii Coulomb-field approximation : pairwise summation : GenBorn Dominy and Brooks.. 1691 GBr6 Tjong and Zhou. 1857 GBSW Im et al. JPCB 111 (2007). 3765 numerical volume integration : GBMV Lee et al. JPC 100 (1996). JPCB 103 (1999).