Title:HPC Analysis of Multiple Binding Sites Communication and Allosteric Modulations in Drug Design: The HSP Case Study
Volume: 17
Issue: 14
Author(s): Federica Chiappori, Luciano Milanesi and Ivan Merelli
Affiliation:
Keywords:
Allostery, drug design, GPU-acceleration, heat shock proteins, high performance computing, molecular dynamics.
Abstract: Allostery is a long-range macromolecular mechanism of internal regulation,
in which the binding of a ligand in an allosteric site induces distant conformational
changes in a distant portion of the protein, modifying its activity. From
the drug design point of view, this mechanism can be exploited to achieve important
therapeutic effects, since ligands able to bind allosteric sites may be designed
to regulate target proteins. Computational tools are a valid support in this sense,
since they allow the characterization of allosteric communications within proteins,
which are essential to design modulator ligands. While considering long-range interactions
in macromolecules, the principal drug design tool available to researcher
is molecular dynamics, and related applications, since it allows the
evaluation of conformational changes of a protein bound to a ligand. In particular, all-atoms molecular
dynamics is suitable to verify the internal mechanisms that orchestrate allosteric communications, in
order to identify key residues and internal pathways that modify the protein behaviour. The problem is
that these techniques are heavily time-consuming and computationally intensive, thus high performance
computing systems, including parallel computing and GPU-accelerated computations, are necessary
to achieve results in a reasonable time. In this review, we will discuss how it is possible to exploit
in silico approaches to characterize allosteric modulations and long-range interactions within proteins,
describing the case study of the Heat Shock Proteins, a class of chaperons regulated by stress conditions,
which is particularly important since it is involved in many cancers and neurodegenerative diseases.
