Biology Reference
In-Depth Information
insights concerning the behavior of simple liquids emerged from their
studies. The next major advance was in 1964, when Rahman carried
out the first simulation using a realistic potential for liquid argon.
9
The
first MD simulation of a realistic system was done by Rahman and
Stillinger in their simulation of liquid water in 1974.
10
The first protein
simulations appeared in 1977 with the simulation of the bovine pan-
creatic trypsin inhibitor (BPTI).
11
The delay between the first simula-
tions of simple liquids and those of proteins reflects the difficulty in
obtaining a reliable set of force field parameters for complex molecules
like proteins.
In Sec. 2, we will present the CHARMM force field as an example
of one of the most widely used semiempirical force fields. The different
types of MD simulations that can be performed using such a force field
are the object of Sec. 3. Free energy simulations, one of the most impor-
tant applications of MD simulations, are presented in Sec. 4. Finally,
Sec. 5 will cover some of the applications that are currently being pur-
sued at the Molecular Modeling Group of the Swiss Institute of
Bioinformatics (SIB).
2. Molecular Force Fields
In this section, we present the statistical mechanics foundations that
provide the theoretical background behind MD simulations and, more
generally, behind all molecular modeling techniques. Molecular model-
ing provides detailed knowledge of the
micro
scopic states of a system
that can be converted into
macro
scopic values using statistical mechan-
ics. For example, the macroscopic pressure of a gas is just the average
force per unit area exerted by its particles as they collide with the con-
tainer walls. Statistical mechanics provides, therefore, the link between
the microscopic world of
in silico
simulations and the macroscopic quan-
tities that can be directly used to compare or predict results from chemical
or biological experiments. In what follows, we will put a major emphasis
on the
affinity
between two molecules, one of the most important
macroscopic quantities for biological and medical applications, and illus-
trate how this quantity can be computed using its statistical mechanics
definition.
