Computational Drug Discovery and Design

5. Elastic network model (ENM) is one of the methods which
   characterize a protein based on its residue interaction network,
   and ENM-based NMA was successfully applied to investigate
   functional dynamics or global motion of proteins [21, 45,
   46 ]. Several methods have been proposed to identify hot spot
   residues or allosteric communication network for protein func-
   tion. Statistical coupling analysis (SCA), which adopts
   sequence covariation analysis based on MSA, has gained grow-
   ing popularity [29, 47, 48]. Perturbative study based on ENM,
   known as structural perturbation method (SPM), has also been
   proposed and provides deep insights into the critical residues
   for maintaining the functional dynamics of an enzyme
   [49]. Although each method can predict few key protein resi-
   dues based on its own concept or algorithm, there are still

Table 2
(continued)

Enhanced MD technique Methodology Applications

Multicanonical ensemble A constant temperature MD on a

deformed PE surface, which

provides a multicanonical ensemble

with a flat energy distribution

The multicanonical ensemble is

subsequently converted into a

canonical ensemble by reweighting

the formula of Ferrenberg and

Swendsen

Larger conformational space

sampling

Random acceleration

molecular dynamics

(RAMD)

Applies a force in a random direction

to COM of the ligand in addition to

its forcefield

Allow ligands to explore possible

dissociation pathways in an unbiased

manner

Ligand dissociation pathways

Replica exchange

molecular dynamics

(REMD)/Parallel

tempering

Run multiple MD simulations with

different values of a specific

exchange variable, i.e., temperature

Based on Metropolis criterion, the

systems states are exchanged

between neighboring simulations at

regular intervals

Free energy landscape, protein

protonation states, and peptide/

protein folding mechanism

Umbrella sampling (US) Employs collective variables

The restraint bias potential (quadratic

or harmonic form) forces the

collective variables in a window to

remain close to the COM

The sets of collective variables must

allow slight overlapping of windows

Ligand binding mechanism, and

ion-induced diffusion in

membrane proteins

468 Shaherin Basith et al.