Molecular Simulation and Systems Biology - Systems Biology: Networks, Models, and Applications - page 86

Figure 3.9 Schematic representation of the replica exchange simulation method.
Independent replicas of the system are simulated at different temperatures
and periodically exchange between temperatures based on Metropolis Monte
Carlo-like acceptance criteria.
initial molecular dynamics simulation is carried out in explicit solvent.
The coordinates of the biomolecule or biomolecular complex (excluding
water and counterions) are saved at regular intervals. Afterward, the
energy of each coordinate is recalculated using a molecular mechanics
force field plus an implicit solvent model. These energies are averaged
and used as an estimate of the free energy of the system. Such methods
are often referred to as ES/IS (explicit solvent/implicit solvent),
MM-PBSA (Molecular Mechanics-Poisson-Boltzman Surface Area), or
MM-GBSA (Molecular Mechanics-Generalized Born Surface Area),
depending on the implicit solvent model used [58,59]. They have
been used to approximate binding free energies of protein-ligand [60],
protein-protein [61], and protein-nucleic acid [3] complexes, as well
as to compare the relative free energies of different biomolecular
conformations [62,63]. All of these methods are empirical, with little
connection to statistical mechanics. As a result, it is difficult or impos-
sible to correctly account for entropic contributions to the free energies
calculated by these approaches, though this is an active area of research
[64]. For biomolecular association, this entropic term is often signifi-
cant, making it the largest source of error in such calculations.
New Applications
Several recent examples of molecular modeling and simulation work
are provided below. This is not an exhaustive list by any means, but
is only meant to provide a flavor for the diversity of approaches that
can be applied to model biological systems.
ELECTROSTATICS OF MICROTUBULES
One example of the modeling of a very large cellular structure is in
the work of Baker et al. [65]. This work characterized the electrostatic