Chemistry Reference
In-Depth Information
and receptor flexibility and corresponding entropic contributions to binding free
energies are important in docking/scoring stages. Since accurate force fields as
well as specialized/extensive sampling procedures are required, rigorous free
energy simulation are far from trivial, requiring expertise and computational
power. Since entropy is physically rooted in statistical thermodynamics, sampling
requirements are crucial. Entropic effects are intimately related with protein
flexibility particularly if ligand binding results in changes of the number of
available torsional degrees of freedom [339-364].
Free energy calculations, at a computational cost, may be useful for assigning
weights to individual receptor conformations as well as better/improved free
energy estimates. Hardware/software computational progress, ongoing
methodological developments, new algorithms and systematic validation against
calorimetric experimental data could eventually yield more routine usage of free
energy calculations. These topics will be discussed in more detail in the following
sections.
MOLECULAR DYNAMICS
In order to predict the interactions of elastic hard spheres models, Alder and
Wainwright performed in the late 1950's one of the first molecular dynamics
(MD) simulations [555-576]. In 1959 Gibson
et al.
performed the MD of a real
material (radiation damage in Cu) [556]. Rahman (dynamics of liquid argon) did
one of the first simulations by MD of a real system in liquid in 1964 [557].
Development in the 1970's, MD simulations were done in more complex systems
(bovine pancreatic trypsin inhibitor) by McCammon. With the increase of
computing power, MD is used in numerous fields of science by different groups
all over the world with an increasing number of publications regarding
applications and theory.
MD, a conformation search procedure, is one of the principal tools in theoretical
studies of biological molecules. It is a conformation space search. In this
procedure, the atoms of the biological macromolecule gets an initial velocity and
then allowed, according to Newtonian mechanics, to evolve in time. Depending
on the simulated temperature, the macromolecule can subsequently, overcome
