ci6b00162_si_001.pdf (2.48 MB)
AlaScan: A Graphical User Interface for Alanine Scanning Free-Energy Calculations
journal contribution
posted on 2016-05-23, 00:00 authored by Vijayaraj Ramadoss, François Dehez, Christophe ChipotComputation
of the free-energy changes that underlie molecular
recognition and association has gained significant importance due
to its considerable potential in drug discovery. The massive increase
of computational power in recent years substantiates the application
of more accurate theoretical methods for the calculation of binding
free energies. The impact of such advances is the application of parent
approaches, like computational alanine scanning, to investigate in
silico the effect of amino-acid replacement in protein–ligand
and protein–protein complexes, or probe the thermostability
of individual proteins. Because human effort represents a significant
cost that precludes the routine use of this form of free-energy calculations,
minimizing manual intervention constitutes a stringent prerequisite
for any such systematic computation. With this objective in mind,
we propose a new plug-in, referred to as AlaScan, developed within
the popular visualization program VMD to automate the major steps
in alanine-scanning calculations, employing free-energy perturbation
as implemented in the widely used molecular dynamics code NAMD. The
AlaScan plug-in can be utilized upstream, to prepare input files for
selected alanine mutations. It can also be utilized downstream to
perform the analysis of different alanine-scanning calculations and
to report the free-energy estimates in a user-friendly graphical user
interface, allowing
favorable mutations to be identified at a glance. The plug-in also
assists the end-user in assessing the reliability of the calculation
through rapid visual inspection.