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Molecular Modeling of Proteins

O. Michielin, SIB/LICR

Molecular Modeling of Proteins
Seminar Plan:
- Central role of partition function
- Review molecular interactions
- Modeling of molecular interactions: CHARMM force field
- Recent techniques:
implicit solvent models
long range electrostatic treatment
- Molecular dynamics simulations
- elements of statistical mechanics
- microcanonical sampling
- canonical sampling
- isothermal-isobaric sampling
- Langevin dynamics
- Other sampling techniques
- Monte-Carlo
- Simulated Annealing (SA)
- Genetic Algorithms (GA)
O. Michielin, SIB/LICR

Molecular Modeling: Introduction
What is Molecular Modeling?
Molecular Modeling is concerned with the description of the atomic
and molecular interactions that govern microscopic and macroscopic
behaviors of physical systems

What is it good for?
The essence of molecular modeling resides in the connection between
the microscopic world and the macroscopic world provided by the
theory of statistical mechanics
(Solvation energy,
affinity between two
proteins, H-H distance,
conformation, ... )

Average of observable
over selected microscopic

O. Michielin, SIB/LICR

Connection micro/macroscopic: intuitive view
E1, P1 ~ e-βE1

Expectation value

〈 O〉=

− E

Z i i

Where Z=

E3, P3 ~ e-βE3


∑i e− E

E2, P2 ~ e-βE2


is the partition function

E4, P4 ~ e-βE4

E5, P5 ~ e-βE5
O. Michielin, SIB/LICR

. Z=∑ i e− E 〈 O〉= 1 − E O e ∑ Z i i i .T Pressure A = -kT ln(Z) Helmoltz free energy O. SIB/LICR .Central Role of the Partition function The determination of the macroscopic behavior of a system from a thermodynamical point of vue is tantamount to computing a quantity called the partition function. from which all the properties can be derived. i Expectation Value 〈 E 〉= ∂ ln  Z =U ∂ Internal Energy p=kT  ∂ln Z   ∂ V N . Michielin.. Z.

T systems .V. and. 2) a method to sample all (or a representative portion) of the microstates accessible to the system in a given macroscopic state. Michielin..performed using semi-empirical force fields CHARMM / Amber / Gromos / ..P. O.canonical sampling for fixed N.T systems .microcanonical sampling for fixed N... SIB/LICR . only numerical approximations are possible Z=∑ i e − E i 1) 2) Numerical approximations require: 1) the computation of the energy of the system for microstate i . in most cases.E systems . i.e: ..V.isothermic-isobaric sampling for fixed N.Computation of the Partition function The partition function is a very complex function to compute.

Michielin. SIB/LICR .Introduction & historical note Theoretical milestones: Newton (1643-1727): Classical equations of motion: F(t)=m a(t) Schrödinger (1887-1961): Quantum mechanical equations of motion: Boltzmann(1844-1906): -ih δt ψ(t)=H(t) ψ(t) Foundations of statistical mechanics Molecular dynamics milestones: Metropolis (1953): Rahman (1964): First MD simulation of proteins The CHARMM general purpose FF & MD program The AMBER general purpose FF & MD program First full QM simulations First QM-MM simulations Proteins Karplus (1977) & McCammon (1977) Karplus (1983): Kollman(1984): Car-Parrinello(1985): Kollmann(1986): Liquids Wood (1957): Alder (1957): First Monte Carlo (MC) simulation of a liquid (hard spheres) First MC simulation with Lennard-Jones potential First Molecular Dynamics (MD) simulation of a liquid (hard spheres) First MD simulation with Lennard-Jones potential O.

SIB/LICR .Intramolecular energy terms associated with the deformation of the electronic structure of the molecule. 3 terms are introduced in all FF: 1) Bond stretch 2) Angle bend 3) Dihedral torsion and a fourth one is often used to maintain planarity 4) Improper torsion O.Molecular Interactions (I) Bonded Interactions: . Michielin.

SIB/LICR . j where e is the dielectric constant. ε and σ O. 1 for vacuum. σij = 1/2(σi + σj) are obtained from the single atom param. and 80 for water 2) van der Waals interactions Attractive part: due to induced-dipole/induced-dipole Repulsive part: due to Pauli exclusion principle Usually represented by the Lennard-Jones potential 12 6 V vdW =∑ 4 ij [  ij / r ij  −  ij /r ij  ] ij εij=(εi εj)1/2.Molecular Interactions (II) Non-Bonded Interactions: . 4-20 for protein core. Michielin.Inter and intramolecular energy terms arising from electrostatics 1) Electrostatic interactions Coulomb law: V Ele=∑ i j qi q j 1 4  r i .

but they result from the two interactions previously described.Collective effect resulting from the energetically unfavorable surface of contact between the water and an apolar medium (loss of water-water Hb) .The apolar medium reorganizes to minimize the water exposed surface Water Oil O.Typical ranges for distance and angle: 2. i.The origin of this interaction is a dipole-dipole attraction . A f 1) Hydrogen bonds (Hb) . the electrostatic and the van der Waals interactions.4 < d < 4.e. SIB/LICR .Derived Interactions Some interactions are often referred to as particular interactions.5Å and 180º < f < 90º -d -d D +d H d 2) Hydrophobic effect . Michielin.Interaction of the type D-H ∙∙∙ A .

The system is divided into a number of atom types that differ by their atomic number and chemical environment.These functions need to be differentiable in order to compute the forces acting on each atom: F=-∇V(r) 2) Ways to compute semi-empirical potential energy functions .Definition of empirical potential energy functions V(r) to model the molecular interactions described previously ..Semi-Empirical Force Fields 1) Goals of semi-empirical force fields . the carbons in C=O or C-C are not of the same type .g. lipids.Parameters are determined so as to reproduce the interactions between the various atom types by fitting procedures . e.. ADN. . theoretical analytical functional forms of the interactions are derived . AMBER) Parametrization available for proteins. SIB/LICR .experimental free energies (GROMOS. sugars.First.experimental enthalpies (CHARMM) . Michielin. O.

j 12 6 ∑ 4 ij [  ij / r ij  −  ij /r ij  ] i j O. SIB/LICR . Michielin.The CHARMM Force Field V  r= ∑ K b b−b 02  ∑ K  −0 2 Bonds  ∑ Impropers  ∑ Dihedrals Angles K  −0 2 K  [1−cosn  − ] qi q j 1 ∑ i  j 4  r i .

00 ! ALLOW PEP                 ! ala dipeptide update for new C VDW Rmin..00    125.00 ! ALLOW PRO PEP                 ! 6­31g* AcProN CA   CA   CA   CA       3. adm jr.0000 ! ALLOW HEM                 ! Heme (6­liganded): substituents (KK 05/13/91) CT3  X    X    CPB    90.0000         0      0.0000         0      0.2000  1   180.20   !  ! for 1­butene.000    120.1000  2   180..00    123.000     1. yin/adm jr.00   35.000     1.3750 ! ALLOW   ARO                 ! benzene. JES 8/25/89 CE1  CE1   440. from propene (JCS)) CA   CA    305. 12/95 CE2  CE1  CT2    48.0000 ! ALLOW HEM                 ! Heme (6­liganded): substituents (KK 05/13/91) HA   C    C    HA     20.20   !  ! for propene.0000         0      0.3350 ! ALLOW ARO HEM                 ! Heme vinyl substituent (KK. from propene.00 ! ALLOW PEP                 ! ala dipeptide update for new C VDW Rmin. 12/95 CE2  CE1  CT3    47.0000 ! ALLOW HEM O. adm jr. 3/3/93c C    N    CP1  C        0.00   2.00 ! ALLOW   ARO                 ! JES 8/25/89 CA   CPT  CPT  CA       3.. yin/adm jr. yin/adm jr.00    126. 12/95 CE1  CT2  CT3    32.8000         0      0.41620 ! ALLOW   ARO                 ! JES 8/25/89 CE1  CE1  CT3    48. yin/adm jr.000     1. 12/95 ANGLES !V(angle) = Ktheta(Theta ­ Theta0)**2 !V(Urey­Bradley) = Kub(S ­ S0)**2 !Ktheta: kcal/mole/rad**2 !Theta0: degrees !Kub: kcal/mole/A**2 (Urey­Bradley) !S0: A !atom types     Ktheta    Theta0   Kub     S0 CA   CA   CA    40.0000         0      0. yin/adm jr.... SIB/LICR . Michielin.3420   !  ! for propene.3400   !  ! for butene. yin/adm jr.000     1. from propene.2000  1   180.1000  2   180.The CHARMM 22 Parameter Set (Sample) BONDS !V(bond) = Kb(b ­ b0)**2 !Kb: kcal/mole/A**2 !b0: A !atom type Kb          b0 C    C     600.0000 ! ALLOW HEM                 ! Heme (6­liganded): porphyrin macrocycle (KK 05/13/91) CPB  X    X    C      90.0000 ! ALLOW   PEP POL ARO                 ! Heme vinyl substituent (KK.. from propene.00   !  ! for 1­butene.50   !  ! for 2­butene.8000  3     0. 3/3/93c C    CT2  NH1  C        0. 12/95 DIHEDRALS !V(dihedral) = Kchi(1 ­ cos(n(chi) ­ delta)) !Kchi: kcal/mole !n: multiplicity !delta: degrees !atom types             Kchi    n   delta C    CT1  NH1  C        0.0000 ! ALLOW HEM                 ! Heme (6­liganded): substituents (KK 05/13/91) CT2  X    X    CPB    90.00    112.4000         0      0.00 ! ALLOW   ARO                 ! JWK 05/14/91 fit to indole IMPROPER !V(improper) = Kpsi(psi ­ psi0)**2 !Kpsi: kcal/mole/rad**2 !psi0: degrees !note that the second column of numbers (0) is ignored !atom types           Kpsi                   psi0 CPB  CPA  NPH  CPA    20. from propene (JCS)) HA   CPA  CPA  CPM    29.. 12/95 CE1  CE2   500.

6700 124.5600 119.00 GROUP ATOM N NH1 -0.115 ATOM HD2 HP 0.9400 112.4501 1.5400 106.3978 1.1900 179.9400 175.3978 1.54 ATOM HH H 0.1200 110.00 GROUP ATOM CD1 CA -0.5113 1.4900 120.0814 1.2700 -116.5200 111.4064 1.115 GROUP ATOM CZ CA 0.51 ATOM O O -0.5232 1.4000 120.4064 1.0900 120.9986 1.4026 1.115 ATOM HE1 HP 0. SIB/LICR .115 GROUP ATOM CD2 CA -0.6900 -178.11 ATOM OH OH1 -0.8000 120.115 GROUP ATOM CE2 CA -0.5113 1.0900 119.1115 1.09 ! O=C | | GROUP ! | HD2 HE2 ATOM CG CA 0.18 ! | | \ __ / \ ATOM HB1 HA 0.7000 120.115 GROUP ATOM CE1 CA -0.4501 1.0000 180.5113 1.6800 180.1119 1.9800 175.5200 106.07 ! | HB1 CD1--CE1 ATOM HA HB 0.4501 1.4022 1.2287 1.3476 1.3100 112.4900 120.3979 1.4600 -175.4068 1.4600 120.9400 120.31 ! HN-N | | ATOM CA CT1 0.4600 120.9594 O.4700 0.43 GROUP ATOM C C 0.4026 1.4513 1.0813 1.1500 112.0000 180.3200 -177.4900 120.0000 -176.47 ! | HD1 HE1 ATOM HN H 0.2500 107.5200 117.3300 117.4300 112.0798 1.51 BOND CB CA CG CB CD2 CG CE1 CD1 BOND CZ CE2 OH CZ BOND N HN N CA C CA C +N BOND CA HA CB HB1 CB HB2 CD1 HD1 CD2 HD2 BOND CE1 HE1 CE2 HE2 OH HH DOUBLE O C CD1 CG CE1 CZ CE2 CD2 IMPR N -C CA HN C CA +N O DONOR HN N DONOR HH OH ACCEPTOR OH ACCEPTOR O C IC -C CA IC -C N IC N CA IC +N CA IC CA C IC N C IC N C IC N CA IC CG CA IC CG CA IC CA CB IC CD1 CB IC CB CG IC CE1 CG IC CB CG IC CE2 CG IC CG CD1 IC CZ CD1 IC CZ CD2 IC CE1 CE2 IC CE1 CZ *N CA C *C +N *CA *CA CB *CB *CB CG *CG CD1 *CD1 CD2 *CD2 CE1 *CE1 *CE2 *CZ OH HN C +N O +CA CB HA CG HB1 HB2 CD1 CD2 CE1 HD1 CE2 HD2 CZ HE1 HE2 OH HH 1.3978 1.0000 180.0500 119.3300 106.0400 180.3600 90.9400 109.115 ATOM HE2 HP 0.3484 1.4500 114.0833 1.09 ! | | // \\ GROUP ! HA-CA--CB--CG CZ--OH ATOM CB CT2 -0.09 ! | HB2 CD2--CE2 HH ATOM HB2 HA 0.4501 1.5700 -0.8100 123.5606 1.4022 1.5600 120.0000 180.5606 1.0000 122.9200 120.3476 1.4064 1.The CHARMM 22 Topology File (Tyr) RESI TYR 0.9400 112.0799 1.5232 1.4063 0. Michielin.115 ATOM HD1 HP 0.5113 1.6400 -178.0000 118.9800 120.7600 120.8100 106.4000 119.5200 117.8900 -123.3400 107.4000 120.5800 119.3300 120.3978 123.5113 1.4900 178.3484 1.

Treatment of long range interactions V  r= ∑ k r r −r 0   ∑ k  −0   2 Bonds  2 Angles ∑ i  j . SIB/LICR .r ij  vdW ∑ Impropers 2 k  −0   12 ∑ Dihedrals k  [1−cos n −] 6 4 ij [  ij /r ij  −  ij / r ij  ] Introduction of dynamical cutoffs Shift/ Switch d O. j  ∑ i  j . Michielin.r ij  Ele qi q j 1 4  r i .

Michielin.Effect of cutoff values on energy calculations 8 Å cutoff No cutoff Elec VdW Total Elec VdW Total O. SIB/LICR .

fixed partial charges allow for conformational polarization but not electronic polarization 2) Quadratic form of potentials: . SIB/LICR . bond creation or deletion Solutions Extended Lagrangian • charges treated as dynamical parameters • QM-MM • Full QM simulations • Car-Parrinello • QM-MM • Full QM simulations • Car-Parrinello • O.Major limitations of current force fields & perspectives Problems 1) No electronic polarization: .problematic far from equilibrium values .

SIB/LICR .Introduction to molecular surfaces Rotating probe: radius 1. Michielin.4 Å Connolly Surface Solvent accessible Surface Van der Waals Surface Definitions: .Solvent: ensemble of probe sphere centers O.Van der Waals: ensemble of van der Waals sphere centered at each atom .Connolly: ensemble of contact points between probe and vdW spheres .

Michielin.Examples of molecular surfaces Van der Waals Connolly (Contact) Solvent accessible O. SIB/LICR .

e=1 e=80 ∇  r ∇  r=Macro r∑ qi n 0i exp− qi r i 2) Other Properties: i) surface curvature ii) residue charge iii) residue conservation iv) .3 V → Blue where f(x) is the solution of the Poisson-Boltzmann eq.Mapping properties on molecular surfaces 1) Electrostatic potential: surface elements are colored according to the value of f(x) with a linear scaling f(x) = -0. SIB/LICR . O. Michielin.3 V → Red f(x) = 0..0 V → Gray f(x) = +0..

Implications of surface properties for ligand binding Acetate (Negative charge) Toluene (Hydrophobic) Meguan (Positive charge) O. SIB/LICR . Michielin.

. Chem.or an approximation.Treatment of the solvent contribution 1) Explicit water molecule model: TIP3P. SIB/LICR . H +d +d H O-d 2) Implicit solvent model: .) ε=1 e=80 For a discussion of theoretical aspects of implicit solvent models.) -SASA potential (Caflish & al. Michielin. 1999.. -ACE potential (Schaeffer & al.) -EEF1 potential (Lazaridis & al.Based on Poisson-Boltzmann Equation: ∇  r ∇  r=Macro r∑ qi n i exp− qi r 0 i . see Roux & Simonson (Biophys... 78:1-20) O..

SIB/LICR .. .Minimal Input for Molecular Modeling 1) Topological properties: description of the covalent connectivity of the molecules to be modeled 2) Structural properties: the starting conformation of the molecule. O. e..g. N. NMR data or a theoretical model 3) Energetical properties: a force field describing the force acting on each atom of the molecules 4) Thermodynamical properties: T0 NV a thermodynamical ensemble that corresponds to the experimental conditions of the system. provided by an X-ray structure.P.T. Michielin.T . N.V.

Michielin. SIB/LICR .Setup of a MD Simulation O.

Michielin.Examples of MD Simulations 1) Simulation of β2 microglobuline 2) Vacuum Simulation of Melan-A Peptide 3) Explicit Solvent Simulation of Melan-A in p-MHC O. SIB/LICR .

Michielin.Energy Landscape Landscape for φ/ψ plane of dialanine Landscape for a protein E φ ψ 3N Spatial coordinates O. SIB/LICR .

E fixed N.Canonical: . rN ) and p= (p1. Examples of thermodynamical ensembles: .Grand Canonic: fixed N..Constant P-T: . . P. where r= (r1...Microcanonical: . P. V. Michielin.. pN ) are the positions and the momenta of the N atoms of the system. p) of the phase space of the system..Review of Statistical Mechanics Thermodynamical Ensembles Definition: a thermodynamical ensemble is a collection of microscopic states that all realize an identical macroscopic state A microscopic state of the system is given by a point (r. T often used in MD often used in MD often used in MD O. .. V. SIB/LICR . T fixed N. T fixed m.

b = 1/KBT with KB the Boltzmann constant. are contained in this function. state (1) and state (2). Cave: if state (1) and (2) are composed of several microscopic states. then the ratio of systems in state (1) and (2) is P1 e − E = − E =e− E − E =e− E P2 e 1 1 2 2 (1) (2) at 300K. a ΔE of 1. All the properties of the system. The partition function is a very complex function to compute. micro or macroscopic. SIB/LICR . Illustration: If a system can have two unique states.3 kcal/mol results in a P1/P2 of 1 log10.Review of Statistical Mechanics Boltzmann Distribution Boltzmann showed that the canonical probability of the microstate i is given by − E e 1 − E P i= = e − E Z ∑e i i j j where Z is the partition function. and in most cases only approximations can be obtained. Michielin. ΔE ≠ ΔG O.

∫ O e − E  p .Review of Statistical Mechanics Expectation value the macroscopic value of an observable. In the case of a continuous microscopic ensemble. or expectation value.r)=K(p)+V(r) In the case of a discret set of microscopic states 〈O〉= 1 −V O e ∑ Z i i i O. is given by the weighted average over all microscopic states of the thermodynamical Ensemble.r  d p d r ∫ e − K  p d p ∫ O e−V r  d r ∫ O e−V r  d r 〈O〉= Ens = Ens Ens ∫ e− E  p . Michielin. r d p d r ∫ e − K  p d p ∫ e−V r  d r Ens Ens = Ens Ens ∫ e−V r  d r = 1 O e−V r d r ∫ Z Ens Ens if O and V are not dependent upon p and E(p. SIB/LICR .

Ergodicity 〈O〉 Ensemble =  1 1 − E  p . Michielin.qe d p d q = Ot dt = 〈O 〉Time ∫ ∫ Z  t =0 The microstates sampled by molecular dynamics are usually a small subset of the entire thermodynamical ensemble. The sampling should reach all important minima and explore them with the correct probability.  Canonic ensemble  P(E) = e-βE  Isothermic-isobaric ensemble  P(E) = e-β(E+PV) Note that the statistical weights are not present in the time average because of this fact.NVE simulations . The validity of this hypothesis depends on the molecular modeling technique and on the quality of the sampling produced. SIB/LICR .Ergodic Hypothesis The ergodic hypothesis is that the ensemble averages used to compute expectation values can be replaced by time averages over the simulation. O.NPT simulations  Microcanonic ensemble  P = cst.NVT simulations . . q O p .

SIB/LICR . e d  d  = ∫ Ot dt = 〈O 〉Time Z  t=0 O.Ergodic Hypothesis: Intuitive view MD Trajectory E NVE simulation in a local minimum 3N Spatial coordinates 〈O〉 Ensemble ?  1 1 − E.  = ∫ O . Michielin.

q˙ t  .Lagrangian and Hamiltonian Formalism Lagrangian Hamiltonian Generalized coordinates q i . . pt . q˙ t  . . the total energy is a constant of motion O.t L q t .3N H qt .t) than H=K+V is the total energy if H≠H(t).t =∑i pi q˙i −Lqt . q˙i i=1. SIB/LICR .3N Definition ∂L q i . t=K −V Equations of Motion d ∂L ∂L  = dt ∂ q˙ i ∂ qi ∂H q˙ i= ∂ pi p˙ i= −∂ H ∂ qi Important properties ∂L ∂L =0 ⇒ ∂ qi ∂ q˙ i is a constant of motion if K≠K(t) and V=V(q. Michielin. p i= ∂ q˙ i i=1.

Gear NVE 2) Canonical ensemble (constant N. SIB/LICR .Verlet.P.V.T) sampling is obtained analogously to canonical sampling by 2 additional degrees of freedom and scaling of time ( T) and space ( P) NV T (Infinite Reservoir) T (Infinite Reservoir) N P (Infinite Reservoir) O. 2) Nose-Hoover: rewriting of the extended system equations to remove time scaling (which is hard to implement in MD) Integration of extended system by Verlet 3) Isothermic-isobaric ensemble (constant N. Leap-Frog. Velocity Verlet.V.MD Techniques (I): Sampling of the various ensembles 1) Microcanonical ensemble (constant N. Michielin.T) sampling is obtained by two methods 1) Nose: additional degree of freedom s acting as an external system on the physical system. s introduces a scaling of time: dt = s dt.E) sampling is obtained by finite difference method integrations of the dynamics equations: .

One of the most stable integrator is that of Verlet: for a small time increment dt. SIB/LICR . . one can use a Taylor expansion of the function r(t): 3N r i t t =r i t v i t t1/ 2 a i t  t 2 r i t− t =r i t −v i t t1/ 2 a i t  t 2 Adding those equations. starting from the initial conditions.In practice. this scheme is applied iteratively. O.MD Techniques (II): Microcanonical sampling p2i For an Hamiltonian of the form H  p .This scheme conserves energy with very good accuracy. one gets r(t+dt) as a function of r(t) and r(t-dt). the Hamilton equations of motion reduce to the Newton equations −∂ pi mi a i=  r  r˙ i= i=1.. . .Positions are correct up to δt4 and velocities to δt2. . r =∑  r 1. r i t t =2 r i t −r i t− t a i t  t 2 .Velocities are postcomputed as v(t) = [r(t+δt)-r(t-δt)] / 2δt.. Michielin. r 3N  2m i=1 i in cartesian coordinates. . N ∂ r mi i Several numerical methods have been developed to integrate these equations..

81(1): 511-19 O. s=∑ i p 2i ps2 q 3N1 kT ln s 2 2Q 2mi s and the equations of motion are pi ∂H q˙ i = = ∂ p i mi s 2 ∂ H ps s˙ = = ∂ ps Q p˙ i = −∂ H −∂  = ∂ qi ∂ qi (Equations for p and q) N p2i −∂ H 1 p˙ s= = ∑[ −3N−1 kT ] ∂ s s i=1 mi s 2 (Equations for ps and s) See Nose 1984. SIB/LICR . where (qi'. J. q . Michielin.t) the virtual variables.t') are the real variables and (qi.pi. p s . The coupling to the physical system is done by an additional degree of freedom s and a scaling of the time such that dt' = dt / s.pi'. The Hamiltonian for the extended system is N H  p .MD Techniques (III): Canonical sampling The system is here coupled to an external infinite constant temperature bath. Chem. Phys. Therefore qi'=qi and pi'=pi/s.

q=∑ i =1 p 2i  q 2mi is the unextended physical Hamiltonian. therefore Z=∫ dp s∫ d p' ∫ d q' ∫ ds s 3N [ H 0  p' . q p s / 2Q3N1 kT ln s− E] 2 N where H 0  p . The volume element dpdq = s3N dp'dq'. q' p s2 /2Q3N 1 kT ln s−E ] and using δ[f(s)] = δ(s-s0) / f'(s0) with s0 the root of f(s).MD Techniques (IV): Derivation of canonical ensemble for HNose The microcanonical partition function associated to the Nose extended Hamiltonian is of the form Z=∫ dp s∫ ds∫ d p ∫ d q  [ H 0  p/ s . on gets Z=C ∫ d p' ∫ d q' exp[−H 0  p' . Michielin. q' /kT ] which is the partition function of the physical system in the canonical ensemble except for a constant factor O. SIB/LICR .

a scaling of time and of the spatial coordinates is performed.V.s.V. The Hamiltonian for the extended system is N H =∑ i p 2i 2 2 p p 1 /3 s V V q  3N1 kT ln s  Pex V 2 2/3 2Q 2W 2mi s V s T (Infinite Reservoir) V P (Infinite Reservoir) O. qi'= V1/3qi and pi'= pi / V1/3s. The coupling to the physical system is done by two additional degrees of freedom s and V.MD Techniques (V): Isothermic-Isobaric sampling The system is here coupled to an external infinite thermostat and to a barostat. Michielin. Analogously.s.t') by the relations dt' = dt / s.pi'. The virtual variables (qi. SIB/LICR .t) are related to the real variables (qi'.pi.

SIB/LICR . Michielin.MD Techniques (VI): NTP ensemble equations of motion Using the extended Hamiltonian with thermostat and barostat coupling N H =∑ i p 2i 2 2 p p 1 /3 s V V q  3N1 kT ln s  Pex V 2 2/3 2Q 2W 2mi s V the following equations of motion are derived q˙ i = pi ∂H = ∂ p i mi V 2 /3 s 2 ∂ H ps s˙ = = ∂ ps Q dV ∂ H pV = = dt ∂ pV W p˙ i = −∂ H −∂  −∂ 1 /3 = = V ∂ qi ∂ qi ∂ qi ' p 2i N p˙ s= −∂ H 1 = ∑[ −3N−1 kT ] (Equations for ps and s) 2/ 3 2 ∂s s i=1 mi V s N p˙V = (Equations for p and q) p 2i ∂ −∂ H 1 = [∑  − qi ' ] (Equations for pV and V) 2 /3 2 ∂V 3V− Pex i =1 mi V s ∂ q i ' O.

q=∑  q is the unextended physical Hamiltonian. SIB/LICR . on can show that N Z=C ∫ d p' ∫ d q' exp[− H 0  p' . V 1/ 3 q s  v P ex V 3N1 kT ln s− E] 2Q 2W p 2i where again H 0  p . i =1 2mi Similarly to the case of the canonical ensemble. q ' Pex V /kT ] which is the partition function of the physical system in the NTP ensemble except for a constant factor O. Michielin.MD Techniques (VII): Derivation of NTP ensemble for HNose The microcanonical partition function associated to the Nose extended NTP Hamiltonian is of the form Z=∫ dpV ∫ dV ∫ dp s∫ ds∫ d p ∫ d q 2 2 p p [ H 0  p /sV 1/ 3 .

−i p i t This equation can for example simulate the friction and stochastic effect of the solvent in implicit solvent simulations. The temperature is adjusted via g and z. This leads to the following equation for the motion of atom i: pi q˙ i = . using the dissipation-fluctuation theorem. Michielin. The stochastic term can improve barrier crossing and hence sampling.a stochastic (random) force: ζ(t) such that <ζ(t)> = 0. Cave: LD does not produce a canonical ensemble O.Other sampling methods: I Langevin Dynamics (LD) In Langevin Dynamics. m p˙ i=F i q . SIB/LICR .a friction force: -γi pi whose direction is opposed to the velocity of atom i . two additional forces are added to the standard force field: .

PC '  −V ' −V  =e P C O. one insures Boltzmann statistics. the new conformer is kept and C' becomes C for next step . a random number.Other sampling methods: II Monte Carlo Simulations and the Metropolis criterion In this sampling method.if V(C') > V(C). in the [0.if V(C') < V(C). r. the new conformer is kept and C' becomes C for next step Using this algorithm. Michielin. additional criteria need to be applied on the new conformer. SIB/LICR . Let C be the initial conformer and C' the randomly modified: . random movements are assigned to the system and the potential energy of the resulting conformer is evaluated. To insure Boltzmann sampling.1] interval is generated and if e-β(V'-V) > r. instead of computing the forces on each atom to solve its time evolution.

SIB/LICR . The sampling obtained by SQ does not follow a Boltzmann distribution. the temperature of the system is raised and cooled several times during a standard MD. LD or MC simulation.a slow (logarithmic) protocol: annealing .Other sampling methods: III Simulated annealing (SA) and simulated quenching (SQ) In these techniques.a fast (exponential) protocol: quenching ? This allows to pass over free energy barriers and to find other minima. Michielin. The sampling obtained by SA generates of an ensemble that tends to a Boltzmann distribution as the cooling time tends to infinity. Two different types of cooling can be achived: . O.

SIB/LICR . constant TP) .following an isothermic and/or isobaric surface (canonic.macroscopic quantities can be obtained as averages over the trajectory.Conclusion Molecular dynamics and other sampling techniques allow: Sampling of the conformational space of the molecule according to various thermodynamical systems: . Michielin.probability of state is related to its free energy .following an isoenergetic surface (microcanonic) . the ergodic hypothesis  〈O〉 Ensemble =〈O〉 Time= 1 Ot dt ∫  t=0 O.

Michielin. SIB/LICR .Some Applications of Molecular Dynamics Techniques 1) Equilibrium MD simulations • • • Expectation values (macroscopic observables) • using ergodic hypothesis Fluctuations • correlation RMSD/B-Factors Free energies • absolute values 2) Quasi-Equilibrium MD simulations • Free energy differences between closely related molecules • conformational free energy change • alchemical mutations 3) Non-Equilibrium MD simulations • Study of large conformational changes • Domain dynamics • Docking • Protein Folding / Stucture predictions O.

E. SIB/LICR .http://www.Allen & Tildesley: Computer Simulations of Liquids . P. Creighton: Proteins. A Set of Lectures Molecular Dynamics . A. Pathria: Statistical Mechanics .html .D.T.embnet.biophysics. 1) Online .pdf 2) Textbooks Statistical Mechanics .info. Structures and molecular properties O. McQuarrie: Statistical Mechanics .D. Feynman: Statistical Mechanics.http://www. Chandler: Introduction to Modern Statistical Mechanics . Jackson: Classical Electrodynamics Protein Structure .R.Tidor & Karplus: Proteins Electrodynamics .