Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis.
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.
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, 77030.
Priyanka
P
Prakash
John F
JF
Hancock
Alemayehu A
AA
Gorfe
D020134:Catalytic Domain; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015335:Molecular Probes / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000737:chemistry*
C117307:KRAS protein, human; D008024:Ligands; D015335:Molecular Probes; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
allosteric sites; drug design; probe-based molecular dynamics simulation