INTRODUCTION MOLECULAR

MECHANICS
 Introduction
Molecular Mechanics or force-field methods use classical type
models to predict the energy of a molecule as a function of its
conformation. This allows predictions of

• Equilibrium geometries and transition states

• Relative energies between conformers or between different
molecules

Molecular mechanics can be used to supply the potential energy

for molecular dynamics computations on large molecules.
However, they are not appropriate (nor are most ab initio
methods!) for bond-breaking reactions.
 STRETCHING
INTERACTIONS
Express energy due to stretching bonds as a Taylor series about
the equilibrium position Re:
2 3
E(R) = k2(R − Re) + k3(R − Re) + ··· (1)

where R is a bond length. The first term should dominate.

How do we get the parameters (k2 and k3, etc.)? Could get
from experiment or by a full quantum mechanical calculation.
The central idea of molecular mechanics is that these
constants are tra n sferrab le to other molecules. Most C–H
bond lengths are 1.06 to 1.10 ˚A in just about any molecule, with
stretching frequencies between 2900 and 3300
cm−1.This strategy is refined using different “atom types.”
FIGURE 1: ATOM
TYPES FOR MM2
 T h e Force-Field
Molecular mechanics expresses the total energy as a sum of
Taylor series expansions for stretches for every pair of bonded
atoms, and adds additional potential energy terms coming from
bending, torsional energy, van der Waals energy,
electrostatics, and cross terms:

E = E str + E bend + E tors + E vdw + E el + E cross . (2)

By separating out the van der Waals and electrostatic terms,

molecular mechanics attempts to make the remaining constants
more transferrable among molecules than they would be in a
spectroscopic force field.
 H i s t o ry
• D. H. Andrews (Phys. Rev., 1930) proposed extending
spectroscopic force field ideas to doing molecular mechanics
• F. H. Westheimer (1940) performed the only molecular
mechanics calculation done by hand to determine the
transition state of a tetrasubstituted biphenyl
• J. B. Hendrickson (1961) performs conformational analysis
of larger than 6 membered rings
• K. B. Wiberg (1965) publishes first general
molecular mechanics type program with ability
to find energy minimum

• N. L. Allinger [Adv. Phys. Org. Chem. 13, 1 (1976)]

 PUBLISHES THE FIRST (MM1) IN
A SERIES OF HIGHLY
POPULAR FORCE FIELDS;THE
SECOND, MM2, FOLLOWS IN 1977

• Many other force field methods have been developed over

the years
 STRETCH
ENERGY

The stretching potential for a bond between atoms A and B is

given by the Taylor series
A B )2 + k A B (R A B − R A B )3 (3)
E(R AB
) = k2A B (R A B −R 0 3 0

+ k4A B (R A B −R 0 )
AB 4
+ ···

and different force field methods retain different numbers of

terms in this expansion (frequently, only the first term is kept).
Note that such expansions have incorrect limiting behavior at
large distances.
 BEND
ENERGY
Bending energy potentials are usually treated very similarly
to stretching potentials; the energy is assumed to increase
quadratically with displacement of the bond angle from
equilibrium.

E bend (θA B C − θ 0A B C ) = k A B C (θA B C − θ 0A B C )2 (5)

An unusual thing happens for θ A B C = 180o: the derivative of

the potential needs to go to zero. This is sometimes enforced.
 Ou t-o f-Plane B e n d in g
The potential for moving an atom out of a plane is sometimes
treated separately from bending (although it also involves
bending). An out-of-plane coordinate (either χ or d) is
displayed below. The potential is usually taken quadratic in
this out-of-plane bend,

E bend−oop (χ B ) = k B (χ B ) 2 . (6)
 Torsional E n e rg y
The torsional energy term attempts to capture some of the
steric and electrostatic nonbonded interactions between two
atoms A and D connected through an intermediate bond B–C.
The torsional angle ω(also often denoted τ ) is depicted below. It
is the angle betwen the two planes defined by atoms A, B, and C
and by B, C, and D.
 van d e r Waals E n e rg y
The van der Waals energy arises from the interactions between
electron clouds around two nonbonded atoms.

S h o r t range: strongly repulsive

I n t e r m e d i a t e range: attractive
Long range: goes to zero
The attraction is due to electron correlation which results in
“dispersion” or “London” forces (instantaneous multipole /
induced multipole).
 ELECTROSTATIC
ENERGY
Electrostatic terms describe the Coulomb interaction between
atoms A and B with partial charges (e.g., in carbonyls),
according to
Q AQB
Eel(R A B ) = , (11)
ǫR AB
where ǫ is an effective dialectric constant which is 1 in vacuum
but higher when there are intermediate atoms or solvent.
Usually ǫ is picked fairly arbitrarily; higher values or so-called
“distance-dependent dialectrics” (ǫ = ǫ0 R AB ) account for
“screening” and kill off the electrostatic contributions faster,
making them easier to compute.
 FITTING ATOMIC
CHARGES
Atoms don’t have charges!! Quantum mechanics tells us
electrons are smeared out, and their charge is shared
among nearby atoms. No unique way to assign electrons
to atoms.
Nevertheless, “atomic charges” are a useful approximation.
Most favored procedure is to perform a quantum computation
and then choose charges that reproduce the quantum electro-
static potential. Restrained Electrostatic Potential (RESP)
procedure used for AMBER force field.
Σnuc ∫
ZA Ψ∗(r′)Ψ(r′) ′
φ esp (r) = − dr (13)
A
|R A − r| |r − r|
′
 I m p r o v ed Electrostatic Po te n tia ls

Electrostatic potentials can be more accurately reproduced by:

• Allowing non-atom-centered charges

• Adding point dipoles, quadrupoles, etc.

Both are employed in Anthony Stone’s Distributed Multipole
Analysis (DMA). However, this does not yet allow the elec-
trostatic variables to change as a function of geometry or to
respond to electrostatic potentials generated by nearby atoms.
This requires polarizable force-fields suchas the fluctuating
charge model.
 CROSS
TERMS
Cross terms are required to account for some interactions
affecting others. For example, a strongly bent H2O molecule
tends to stretch its O–H bonds. This can be modeled by cross
terms such as
Σ Σ
E str/bend = k A B C (θA B C −θ 0A B C ) (R A B − R 0A B ) + (R B C − R BC
0 )
(23)
Other cross terms might include stretch-stretch, bend-bend,
stretch-torsion, bend-torsion, etc. Force field models vary in
what types of cross terms they use.
 H e a t s of F o r ma ti on
∆ H f is the heat conent relative to the elements at standard
state at 25o C (g). This is a useful quantity for comparing the
energies of two conformers of a molecule or two different
molecules.
Bond energy schemes estimate the overall ∆ H f
by adding tabulated
contributions from each type of bond. This works
acceptably well for strainless systems.
Molecular mechanics adds steric energy to the bond/structure
increments to obtain better estimates of ∆ H f .
The bare molecular mechanics energy is not a meaningful
quantity for comparing different molecules.
Table 1: Average errors in heat of formations (kcal/mol) by
MM2a

Compound type Avg error ∆ H f

Hydrocarbons 0.42
Ethers and alcohols 0.50
Carbonyls 0.81
Aliphatic amines 0.46
Aromatic amines 2.90
Silanes 1.08
aTable 2.6 from Jensen’s Introduction to Computational Chem-
istry.
 Different Force Field M e t h o d s
Class I Methods: Higher order terms and cross terms. Higher
accuracy, used for small or medium sized molecules. Examples:
Allinger’s MM1-4, EFF, and CFF.
Class II Methods: For very large molecules (e.g., proteins).
Made cheaper by using only quadratic Taylor expansions
and neglecting cross terms. Examples: AMBER, CHARMM,
GROMOS, etc. Made even cheaper by using “united atoms.”
 H y b r i d Force F i e l d /E lectro n ic S t r u c t u r e M e t h o d s
Treat “uninteresting” parts of the molecule by force field
methods and “interesting” parts by high-accuracy electronic
structure methods. This approach is useful for systems
where part of the molecule is needed at high accuracy or for
which no force field parameters exist (e.g., metal centers in
metalloenzymes).

Examples: Morokuma’s ONIOM method; QM/MM methods.

 Q M / M M Approaches
E total = E Q M + E M M + E Q M / M M (24)
• Mechanical embedding: Include bonded and steric inter-
actions between QM and MM regions, and maybe assign
partial charges to the QM atoms
• Electronic embedding: Also add partial charges on MM
atoms to QM computation
• Polarizable embedding: Also allow QM atoms to polarize
MM region (only applies to polarizable force fields or
Gordon’s effective fragment method)
If the QM/MM boundary cuts covalent bonds, dangling bonds
are terminated by so-called “link atoms” (typically hydrogen).
SUMBER:
C. David Sherrill, Introduction to Molecular Mechanics School of Chemistry and
Biochemistry Georgia Institute of Technology