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

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