- MARTINI is a widely used CG model but cannot be used for
modeling backbone conformational transitions owing to the
use of an elastic network model (ENM) to restrain protein
secondary structure to its starting conformation [169].
A recent development of MARTINI has been able to fold
some protein fragments by replacing the ENM restraints with
a contact map [170]. - To perform NMA on an atomistic protein model a powerful
minimization is required (to find the bottom of the approxi-
mated harmonic basin) followed by diagonalization of the
second derivative of the potential energy (3 N3 N Hessian
matrix). - Recent application code libraries such as Bio3D and ProDy
offer advanced combinations of ENMs like pathway sampling
strategies or correlation analyses, and can be used to build
combinations for custom pipelines [164, 165]. - The Gaussian height is reduced over time such that the simula-
tion is forced to converge as the height tends to zero. - There is continual exploration of the optimal arrangements for
replica-exchange but generally exchanges are made every
2–10,000 time steps and optimized such that at least 30% of
exchanges are accepted [171]. - Temperature replica-exchange with even moderately sized,
explicitly solvated, systems requires many replicas owing to
the high heat capacity of water. - The experiences of the current authors suggest that biasing
over multiple replicas, each with an uncorrelated driven vari-
able, is often able to explore protein conformational space in a
very powerful way but can be difficult to converge. - There are currently at least five academic codes for managing
large adaptive celling calculations [172–177]. - A single Anton 2 computer can produce a ~115 us simulation
per day on the standard industry test system. It should be
noted that many important biological processes take place
over much longer timescales. Anton 2 has been optimized for
simulations of large models (~700,000 atoms), which fits with
their aims of “investigating the mechanisms of several pharma-
ceutically relevant cellular receptors, transport proteins, and
enzymes” as some of the suggested systems of study would
be very large. - For example Morphic Therapeutics focused entirely on a very
detailed understanding of the molecular mode of action of the
integrin family of proteins to achieve a first in class therapeutic.
Computational Study of Protein Conformational Transitions 357