Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis

Proteins
Priyanka PrakashAlemayehu A Gorfe

Abstract

We have used probe-based molecular dynamics (pMD) simulations to search for interaction hotspots on the surface of the therapeutically highly relevant oncogenic K-Ras G12D. Combining the probe-based query with an ensemble-based pocket identification scheme and an analysis of existing Ras-ligand complexes, we show that (i) pMD is a robust and cost-effective strategy for binding site identification, (ii) all four of the previously reported ligand binding sites are suitable for structure-based ligand design, and (iii) in some cases probe binding and expanded sampling of configurational space enable pocket expansion and increase the likelihood of site identification. Furthermore, by comparing the distribution of hotspots in nonpocket-like regions with known protein- and membrane-interacting interfaces, we propose that pMD has the potential to predict surface patches responsible for protein-biomolecule interactions. These observations have important implications for future drug design efforts and will facilitate the search for potential interfaces responsible for the proposed transient oligomerization or interaction of Ras with other biomolecules in the cellular milieu.

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Citations

Jan 28, 2016·Chemical Reviews·Shaoyong LuJian Zhang
Oct 22, 2015·Acta Biochimica Et Biophysica Sinica·Michael McCarthyAlemayehu A Gorfe
Oct 28, 2015·PLoS Computational Biology·Priyanka PrakashAlemayehu A Gorfe
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May 13, 2021·The Journal of Physical Chemistry. B·Meryem ErenOzlem Keskin
Sep 27, 2019·The Journal of Physical Chemistry. B·Priyanka Prakash, Alemayehu A Gorfe

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