C7790 Introduction to Molecular Modelling -1C7790
Introduction to Molecular
Modelling
TSM Modelling Molecular Structures
Petr Kulhánek
kulhanek@chemi.muni.cz
National Centre for Biomolecular Research, Faculty of Science
Masaryk University, Kamenice 5, CZ-62500 Brno
PS/2021 Present Form of Teaching: Rev2
Lesson 24
Molecular Mechanics I
C7790 Introduction to Molecular Modelling -2-
Context
microworldmacroworld
equilibrium (equilibrium constant)
kinetics (rate constant)
free energy
(Gibbs/Helmholtz)
partition function
phenomenological thermodynamics
statistical thermodynamics
microstates
(mechanical properties, E)
states
(thermodynamic properties, G, T,…)
microstate ≠ microworld
Description levels (model chemistry):
• quantum mechanics
• semiempirical methods
• ab initio methods
• post-HF methods
• DFT methods
• molecular mechanics
• coarse-grained mechanics
Structure
EnergyFunction
Simulations:
• molecular dynamics
• Monte Carlo simulations
• docking
• …
C7790 Introduction to Molecular Modelling -3𝐸
𝑘(𝐑) = 𝐸 𝑏𝑜𝑛𝑑𝑠 + 𝐸 𝑎𝑛𝑔𝑙𝑒𝑠 + 𝐸𝑡𝑜𝑟𝑠𝑖𝑜𝑛𝑠 + 𝐸𝑒𝑙𝑒 + 𝐸 𝑣𝑑𝑤+. . .
)()()(ˆ
ekkek EH rRr RR
 =
Molecular Mechanics
Schrodinger equation - quantum mechanical description
bonded contributions non-bonded contributions
Classical physics - mechanical description
approximation
electron motions is omitted
(electron motions is implicitly included in empirical parameters)
C7790 Introduction to Molecular Modelling -4-
Nomenclature
𝐸 𝑘(𝐑) = 𝐸 𝑏𝑜𝑛𝑑𝑠 + 𝐸 𝑎𝑛𝑔𝑙𝑒𝑠 + 𝐸𝑡𝑜𝑟𝑠𝑖𝑜𝑛𝑠 + 𝐸𝑒𝑙𝑒 + 𝐸 𝑣𝑑𝑤+. . .
https://en.wikipedia.org/wiki/Force_field_(chemistry)
https://en.wikipedia.org/wiki/Coarse-grained_modeling
https://en.wikipedia.org/wiki/Molecular_mechanics
Molecular mechanics uses classical mechanics to model molecular systems. The Born–
Oppenheimer approximation is assumed valid, and the potential energy of all systems is
calculated as a function of the atomic coordinates using force fields.
Coarse-grained modeling, coarse-grained models, aim at simulating the behavior of
complex systems using their coarse-grained (simplified) representation. Coarse-grained
models are widely used for molecular modeling of biomolecules at various granularity
levels.
In the context of chemistry and molecular modelling, a force field is a computational
method that is used to estimate the forces between atoms within molecules and between
molecules.
More precisely, the force field refers to the functional form and parameter sets used to
calculate the potential energy of a system of atoms or coarse-grained particles.
+ parameters
C7790 Introduction to Molecular Modelling -5Bonded
Contributions
C7790 Introduction to Molecular Modelling -6Bonded
Contributions
Bond stretching
Angle bending
Bond rotation
empirical parameters
Main contributions
C7790 Introduction to Molecular Modelling -7Bond
stretching
Harmonic potential
𝐸 𝑏(𝑟) =
1
2
𝐾 𝑟 − 𝑟0
2
➢ The simplest description of a valence bond deformation is provided by the harmonic
approximation.
➢ Valence bond deformation is then effectively described in the limit of Hooke's law.
➢ Hooke's law is a law of physics that states that the force (𝐹𝑠) needed to extend or
compress a spring by some distance (Δ𝑟) scales linearly with respect to that distance.
The scaling factor (𝐾) is a stiffness constant.
𝑑𝐸 𝑏(𝑟)
𝑑𝑟
= −𝐹 = 𝐹𝑠 = 𝐾 𝑟 − 𝑟0
𝐹𝑠 = 𝐾Δ𝑟
restoring force
deformation force
equilibrium bond distance
stiffness (force constant)
➢ Higher order potentials such as a cubic potential can
be used, but they exhibit catastrophic behavior at
longer stretching distances. Why?
C7790 Introduction to Molecular Modelling -8Bond
stretching, cont.
Morse potential
( )
( )2
0
1)( rra
e eDrV −−
−=
Harmonic potential
( )2
0
2
1
)( rrKrV −=
➢ The harmonic potential does not have dissociation limit. Thus, force fields employing
the harmonic approximation cannot describe reactivity.
➢ The reactivity is difficult to describe even with Morse potential properly, a noticeable
exceptions are ReaxFF (reactive force field) and EVB (empirical valence bond).
Disadvantage of Morse potential
• more parameters are needed
• more computationally demanding
C7790 Introduction to Molecular Modelling -9𝐸
𝑎 =
1
2
𝐾 Θ − Θ0
2
Angle bending
➢ The simplest description of a valence angle deformation is provided by the harmonic
approximation similarly to a valence bond.
equilibrium valence anglestiffness (force constant)
➢ Alternative forms
➢ GROMOS Forcefield
➢ Higher order potentials
➢ Cross-terms, which describes coupling between bond stretching and angle bending.
𝐸 𝑎 =
1
2
𝐾[cos(Θ) − cos(Θ0)]2
this form avoids singularities in
gradient calculations for straight
angles (180°)
cos(Θ)=
𝒗 𝐵𝐴. 𝒗 𝐵𝐶
𝒗 𝐵𝐴 𝒗 𝐵𝐶
𝒗 𝐵𝐴
𝒗 𝐵𝐶
B
A
C
Θ
C7790 Introduction to Molecular Modelling -10Bond
rotation
A
B
C
D
𝜑
Torsion angle (dihedral angle) is signed angle between two planes A-B-C and B-C-D.
cos(Θ)=
𝒏 𝐴𝐵𝐶. 𝒏 𝐵𝐶𝐷
𝒏 𝐴𝐵𝐶 𝒏 𝐵𝐶𝐷
(+) clock-wise(-) anti clock-wise
only [0, p]
[0, p][-p, 0]
normal vectors (perpendicular
to the plane)
𝒏 𝐴𝐵𝐶 = 𝒗 𝐵𝐴 × 𝒗 𝐵𝐶
Bond rotations can be described by torsion
(dihedral) angles.
C7790 Introduction to Molecular Modelling -11➢
Torsional energy can be approximated by a Fourier series.
➢ Due to computational complexity, the length of the Fourier series is truncated. Typical
lengths are up 𝐾 = 4.
Bond rotation, cont.
𝐸𝑡 = ෍
𝑛=1
𝐾
𝑉𝑛
2
[1 − cos(𝑛𝜑 − 𝛾𝑛)]
phaseamplitude
length of the Fourier series
This equation is for a single torsion!!!!
torsional energy is a periodic function
C7790 Introduction to Molecular Modelling -12➢
Angle bending and bond rotations are not able to properly describe out-of-plane
deformations.
➢ Out-of-plane deformations are observed in planar parts of molecules such as aromatic
rings or peptide bonds (conjugated system).
➢ There are several geometrical descriptions of out-of-plane deformations (deviation from
the plane or improper torsion).
➢ The deformation energy is expressed as either harmonic potential or a Fourier series.
Out-of-plane deformations
A
B
D
𝜑
C
Planes:
A-B-C
B-C-D
improper torsion
C7790 Introduction to Molecular Modelling -13-
Non-Bonded
(Non-covalent)
Contributions
C7790 Introduction to Molecular Modelling -14𝐸
𝑣𝑑𝑤 = ෍
𝑖=1
𝑁
෍
𝑗=𝑖+1
𝑁
4𝜀𝑖𝑗
𝜎𝑖𝑗
𝑟𝑖𝑗
12
−
𝜎𝑖𝑗
𝑟𝑖𝑗
6
𝐸𝑒𝑙𝑒 = ෍
𝑖=1
𝑁
෍
𝑗=𝑖+1
𝑁
1
4𝜋𝜀 𝑜
𝑞𝑖 𝑞 𝑗
𝑟𝑖𝑗
Non-bonded Contributions
Electrostatic interactions
van der Waals interactions
empirical parameters
N – number of atoms
Main contributions
C7790 Introduction to Molecular Modelling -15Excluded
Interactions
➢ Non-bonded interactions are computed between ALL atoms except of those pairs, which
are explicitly described by bonded terms.
➢ Non-bonded interactions are thus both of intra and intermolecular origin.
➢ Excluded interactions are:
➢ 1-2 (bond stretching)
➢ 1-2-3 (angle bending)
➢ 1-2-3-4 (bond rotations) are not fully excluded but instead they are scaled
C7790 Introduction to Molecular Modelling -16Electrostatic
interactions
𝐸𝑒𝑙𝑒 = ෍
𝑖=1
𝑁
෍
𝑗=𝑖+1
𝑁
1
4𝜋𝜀 𝑜
𝑞𝑖 𝑞 𝑗
𝑟𝑖𝑗
➢ Electron density and positively charged nuclei of atoms are approximated by point
charges.
➢ Interaction between point charges is provided by Coulomb potential.
➢ This simple model does not describe induction and penetration effect.
➢ Penetration electrostatic energy is always attractive and is consequence of overlap of
smeared electron density and point nuclear charges at short distances. However, the
effect of penetration energy is absorbed in LJ potential in the simple FF.
➢ Polarizable force fields
➢ they try to include effect of induction employing polarizable electrostatic models
(induced dipoles, Drude oscillator, fluctuating charges, etc…)
➢ more computationally demanding, improvement is questionable
C7790 Introduction to Molecular Modelling -17Point
charges
Atomic partial charges are not observable. Rather, they are (crude) approximation of
electron density and point nuclear charges.
Point charges must describe well electrostatic potential of molecules and their interactions.
Sources of charges are QM calculations:
➢ Restrained ElectroStatic Potential Charges (RESP) derived from ESP charges.
➢ RESP corrects chemically non-intuitive charges on carbon atoms.
➢ RESP/ESP procedure fails on large structures with buried atoms.
➢ CM5 charges
➢ CHelpG charges
➢ DDEC6 charges
➢ others …
Abdel-Azeim, S. Revisiting OPLS-AA Force Field for the Simulation of Anionic Surfactants in
Concentrated Electrolyte Solutions. J. Chem. Theory Comput. 2020, 16 (2), 1136–1145.
https://doi.org/10.1021/acs.jctc.9b00947.
C7790 Introduction to Molecular Modelling -18ESP
charges
ESP charges (ElectroStatic Potential) are charges derived from electrostatic potential. The
principle of charge calculation consists of two steps:
1. calculation of electrostatic potential VQM from wave function on discretized
molecular envelope (set of points)
2. finding point atomic charges that create electrostatic potential VPC which is in the
best agreement with the quantum mechanical potential (least squares method)
pQMV ,→ kpPC qV ,
( ) min!
2
,, =−p
pPCpQM VV
is searched by least
squares method
http://biomodel.uah.es/Jmol/surfaces/inicio.htm
ESP charges and their derivatives are used in molecular
mechanics because, by their nature, they describe well
electrostatic properties of molecules/system.
C7790 Introduction to Molecular Modelling -19van
der Waals interactions
van der Walls interactions are very often described
by Lenard-Jones potential.
𝐸 𝑣𝑑𝑤 = ෍
𝑖=1
𝑁
෍
𝑗=𝑖+1
𝑁
𝜀𝑖𝑗
𝑅 𝑚,𝑖𝑗
𝑟𝑖𝑗
12
− 2
𝑅 𝑚,𝑖𝑗
𝑟𝑖𝑗
6
𝐸 𝑣𝑑𝑤 = ෍
𝑖=1
𝑁
෍
𝑗=𝑖+1
𝑁
4𝜀𝑖𝑗
𝜎𝑖𝑗
𝑟𝑖𝑗
12
−
𝜎𝑖𝑗
𝑟𝑖𝑗
6
repulsive part
(Pauli repulsion)
attractive part
(dispersion)
𝜎𝑖𝑗
𝑅 𝑚,𝑖𝑗
Alternative forms:
𝐸𝑣𝑑𝑤 = ෍
𝑖=1
𝑁
෍
𝑗=𝑖+1
𝑁
𝐴𝑖𝑗
𝑟𝑖𝑗
12
−
𝐵𝑖𝑗
𝑟𝑖𝑗
6
"Better" models:
➢ exp-6 potential (however,
it is unphysical at short
distances)
C7790 Introduction to Molecular Modelling -20Combining
rules
In computational chemistry and molecular dynamics, the combination rules or combining
rules are equations that provide the interaction energy between two dissimilar nonbonded
atoms, usually for the part of the potential representing the van der Waals
interaction.
Combining rules considerably reduce the number of needed parameters.
https://en.wikipedia.org/wiki/Combining_rules
Lorentz-Berthelot rules
𝜀𝑖𝑗 = 𝜀𝑖𝑖 𝜀𝑗𝑗
𝜎𝑖𝑗 =
𝜎𝑖𝑖 + 𝜎𝑗𝑗
2
arithmetic mean
geometric mean
LB rules are rather inaccurate. However, their success relies on the fact that the number of
unlike interactions is considerably higher that between like atoms.
Then, like parameters are optimized in such a way that resulting unlike parameters
performs well. Side outcome is that like parameters alone do not perform well.
C7790 Introduction to Molecular Modelling -21FF
Parameters
C7790 Introduction to Molecular Modelling -22Atom
Types
➢ Force Filed parameters are required for:
➢ each valence bond (Kb, r0)
➢ each valence angle (Ka, Q0)
➢ each torsion angle (series of Vn, g)
➢ each atom (qi, eii, sii)
Atom Types:
➢ Atoms types group atoms within the similar chemical environment
This is impractical due large number
of required parameters!!!
solution
PARM99 for DNA,RNA,AA, organic molecules, TIP3P wat. Polariz.& LP incl.02/04/99
C 12.01 0.616 ! sp2 C carbonyl group
CA 12.01 0.360 sp2 C pure aromatic (benzene)
CT 12.01 0.878 sp3 aliphatic C
CV 12.01 0.360 sp2 arom. 5 memb.ring w/1 N and 1 H (HIS)
CW 12.01 0.360 sp2 arom. 5 memb.ring w/1 N-H and 1 H (HIS)
C* 12.01 0.360 sp2 arom. 5 memb.ring w/1 subst. (TRP)
CY 12.01 0.360 nitrile C (Howard et al.JCC,16,243,1995)
CZ 12.01 0.360 sp C (Howard et al.JCC,16,243,1995)
H 1.008 0.161 H bonded to nitrogen atoms
HC 1.008 0.135 H aliph. bond. to C without electrwd.group
H1 1.008 0.135 H aliph. bond. to C with 1 electrwd. group
HA 1.008 0.167 H arom. bond. to C without elctrwd. groups
C7790 Introduction to Molecular Modelling -23Assigning
Parameters - I
input
molecule
atom types
template library
(atom types + partial charges)
topology
coordinates
Force field
(FF parameters)
partial charges
atom names -> atom types
predefined template libraries for components of biomolecular structures
➢ aminoacid residues
➢ nucleotides
C7790 Introduction to Molecular Modelling -24Assigning
Parameters - II
input
molecule
atom types
topology
coordinates
external QM /
internal EEM
calculations
Force field
(FF parameters)
partial charges
➢ typically, small organic molecules
➢ partial atomic charges are calculated independently
C7790 Introduction to Molecular Modelling -25Parameter
optimization
Parameters can be derived from:
➢ experimental data
➢ bulk properties (density, etc.)
➢ thermodynamics (binding affinities)
➢ experimental geometries (equilibrium bond lengths and valence angles)
➢ vibrational spectra (force constants)
➢ computational data (QM calculations)
➢ geometry (equilibrium values)
➢ vibrational analysis (force constants)
➢ potential energy scans for bond rotations
Transferability of parameters is key for general use in modelling.
C7790 Introduction to Molecular Modelling -26Common
Force Fields
AMBER (Assisted Model Building and Energy Refinement) – widely used for proteins and
DNA.
CHARMM (Chemistry at HARvard Molecular Mechanics) – originally developed at Harvard,
widely used for both small molecules and macromolecules
GROMOS (GROningen MOlecular Simulation) – a force field that comes as part of the
GROMOS software, a general-purpose molecular dynamics computer simulation
package for the study of biomolecular systems. GROMOS force field A-version has been
developed for application to aqueous or apolar solutions of proteins, nucleotides, and
sugars. A B-version to simulate gas phase isolated molecules is also available.
MMFF (Merck Molecular Force Field) – developed at Merck for a broad range of molecules.
OPLS (Optimized Potential for Liquid Simulations) (variants include OPLS-AA, OPLS-UA,
OPLS-2001, OPLS-2005, OPLS3e, OPLS4) – developed by William L. Jorgensen at the
Yale University Department of Chemistry.
GAFF – a general AMBER force field was developed for rational drug design. GAFF is
compatible with the AMBER force field, and it has parameters for almost all the organic
molecules made of C, N, O, H, S, P, F, Cl, Br and I. As a complete force field, GAFF is
suitable for study of a great number of molecules (such as database searching) in an
automatic fashion.
https://en.wikipedia.org/wiki/Force_field_(chemistry)