Molecular Simulation and Systems Biology - Systems Biology: Networks, Models, and Applications - page 80

sheets of acidic head groups form that are in contact with water, and
the hydrophobic chains are contained between these layers. Lipid
bilayers are a primary constituent of the cell membranes of all cells.
Cells have a number of other molecules dissolved within these bilay-
ers, such as proteins that are involved in controlled transport of
molecular material into and out of the cell (transport proteins), and
in the sensing of material in the cell's environment and the transfer
of information from outside to inside the cell (signaling proteins).
Membranes and their components are extremely important since most
drugs work by affecting the transfer of material or information across
the membrane.
Cell membranes contain a number of other molecules, such as
cholesterol, and it is believed that the cholesterol has a profound effect
on the structure and dynamical nature of the membrane. Cholesterol
also surrounds and affects the behavior of membrane-bound proteins.
The exact role of cholesterol and its importance to the cell membrane is
not fully understood, and one important use of simulation is to study
the cholesterol-induced dynamics and organization of material in the
membrane [23].
A Short Historical Overview
Arguably, the first biomolecular simulation was a simulation of 216
water molecules for 2.17 picoseconds by Rahman and Stillinger in
1971 [24]. This simulation demonstrated that liquid water contains
an extensive, but dynamic, network of water-water hydrogen bonds
that fluctuate on a time scale of several picoseconds. Diffusion in water
was also observed to proceed by a continuous, cooperative flow of
several molecules of water rather than by a single molecule hopping
from one site to another in the liquid.
The first detailed dynamical simulation of a protein was carried out
in 1977 [25]. The protein in question was bovine pancreatic trypsin
inhibitor (BPTI, PDB [26] id 1PTI), and it was simulated for a total of
8.8 ps in vacuum. Despite the short simulation time, it was possible
to observe significant, low-frequency anharmonic motions of the
protein. The first simulation of a protein in water occurred many years
later with the simulation of BPTI in a hydrated protein crystal by van
Gunsteren et al. [27].
In addition to dynamical properties, molecular simulations can
also be used to study the function of proteins. For example, simulations
can be used to determine the relative affinity of a protein for two
different ligands. The first such binding free energy calculation was
carried out to compare two ligands binding to the protein thermolysin
by Bash et al. in 1987 [28].
Beyond ligand binding, proteins also act as enzymes to accelerate
chemical reactions. These reaction processes involve the breaking and