Lecture 01y

Overview of Molecular Modeling
CHEM 430
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
Macroscopic Average of observable

observable over selected microscopic
(Solvation energy, states
affinity between two
proteins, H-H distance,
conformation, ... )
[Blatantly Stolen from Bill Goddard, Computational Chemistry GRC, circa 1986]
Experiment vs. Simulation vs. Theory
Types of Simulation Systems
Model Accuracy vs. Computing Resources
Molecular Motion Time Scales
Types of Molecular Surfaces
Rotating probe: radius 1.4 Å
Connolly Surface
Solvent accessible
Surface
Van der Waals

Surface
Definitions:
- Van der Waals: ensemble of van der Waals sphere centered at each atom
- Connolly: ensemble of contact points between probe and vdW spheres
- Solvent: ensemble of probe sphere centers
Examples of Molecular Surfaces
Van der Waals
Connolly
(Contact)
Solvent accessible
Connection between Microscopic & Macroscopic
E1, P1 ~ e-βE1
Expectation value E2, P2 ~ e-βE2
1
〈 O〉= ∑ O
Z i i
e
− E i
E3, P3 ~ e-βE3
Where Z= ∑i e− E i
is the partition function E4, P4 ~ e-βE4
E5, P5 ~ e-βE5
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, Z, from which all the properties can be
derived.
Z=∑i e− E i
1
〈 O〉= ∑ O
Z i i
e
− E i
...
Expectation Value
∂ln Z 
〈 E 〉= ∂ ln  Z =U p=kT   A = -kT ln(Z)
∂ ∂ V N ,T
Internal Energy Pressure Helmoltz free energy

Computation of the Partition Function
The partition function is a very complex function to compute, and, in
most cases, 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

- performed using semi-empirical force fields
CHARMM / Amber / Gromacs / NAMD / Tinker ...
2) a method to sample all (or a representative portion) of the
microstates accessible to the system in a given macroscopic
state, i.e:
- microcanonical sampling for fixed N,V,E systems
- canonical sampling for fixed N,V,T systems
- isothermic-isobaric sampling for fixed N,P,T systems
- other specialized ensembles...
Molecular Simulation: Historical Dates of Note
Theoretical milestones:
Newton (1643-1727): Classical equations of motion: F(t)=m a(t)
Schrödinger (1887-1961): Quantum mechanical equations of motion:
-ih δt ψ(t)=H(t) ψ(t)
Boltzmann(1844-1906): Foundations of statistical mechanics
Molecular dynamics milestones:

Metropolis (1953): First Monte Carlo (MC) simulation of a liquid
(hard spheres)
Wood (1957): First MC simulation with Lennard-Jones potential
Liquids
Alder (1957): First Molecular Dynamics (MD) simulation of
a liquid (hard spheres)
Rahman (1964): First MD simulation with Lennard-Jones potential
Karplus (1977) & First MD simulation of proteins

McCammon (1977)
Proteins
Karplus (1983): The CHARMM general purpose FF & MD program
Kollman(1984): The AMBER general purpose FF & MD program
Car-Parrinello(1985): First full QM simulations
Kollmann(1986): First QM-MM simulations
Structural Characterization via RDF Analysis
Implicit Solvation Models
Treatment of the Solvent Contribution
1) Explicit water molecule model: TIP3P, ...

+d +d
H H
O-d
2) Implicit solvent model:
- Based on Poisson-Boltzmann Equation:
∇  r ∇  r=Macro r∑ qi n i exp− qi r

0
- or an approximation...
-ACE potential (Schaeffer & al.)
-SASA potential (Caflish & al.)
-EEF1 potential (Lazaridis & al.)
ε=1 e=80
For a discussion of theoretical aspects of implicit solvent models,
see Roux & Simonson (Biophys. Chem. 1999, 78:1-20)
Double Dynamic Programming Alignment Algorithms
Rosetta Uses Fragment Library + Monte Carlo Search
AlphaFold2 Structure Predictions from CASP14

Lecture 01y

Uploaded by

Lecture 01y

Uploaded by

Overview of Molecular Modeling

What is it good for?

The essence of molecular modeling resides in the connection between

Macroscopic Average of observable

Rotating probe: radius 1.4 Å

Van der Waals

Expectation value E2, P2 ~ e-βE2

is the partition function E4, P4 ~ e-βE4

The determination of the macroscopic behavior of a system from a

Internal Energy Pressure Helmoltz free energy

1) the computation of the energy of the system for microstate i

Molecular dynamics milestones:

Karplus (1977) & First MD simulation of proteins

1) Explicit water molecule model: TIP3P, ...

- Based on Poisson-Boltzmann Equation:

∇  r ∇  r=Macro r∑ qi n i exp− qi r

You might also like