title: Intrinsic K-Ras dynamics: A novel molecular dynamics data analysis method shows causality between residue pair motions.
abstract: K-Ras is the most frequently mutated oncogene in human cancers, but there are still no drugs that directly target it in the clinic. Recent studies utilizing dynamics information show promising results for selectively targeting mutant K-Ras. However, despite extensive characterization, the mechanisms by which K-Ras residue fluctuations transfer allosteric regulatory information remain unknown. Understanding the direction of information flow can provide new mechanistic insights for K-Ras targeting. Here, we present a novel approach -conditional time-delayed correlations (CTC) - using the motions of all residue pairs of a protein to predict directionality in the allosteric regulation of the protein fluctuations. Analyzing nucleotide-dependent intrinsic K-Ras motions with the new approach yields predictions that agree with the literature, showing that GTP-binding stabilizes K-Ras motions and leads to residue correlations with relatively long characteristic decay times. Furthermore, our study is the first to identify driver-follower relationships in correlated motions of K-Ras residue pairs, revealing the direction of information flow during allosteric modulation of its nucleotide-dependent intrinsic activity: active K-Ras Switch-II region motions drive Switch-I region motions, while α-helix-3L7 motions control both. Our results provide novel insights for strategies that directly target mutant K-Ras.
authors.affiliation: Department of Chemical and Biological Engineering, College of Engineering, Koç University, Rumelifeneri Yolu, 34450, Sarıyer, Istanbul, Turkey.|Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Sezen
authors.initials: S
authors.lastname: Vatansever
authors.affiliation: Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Zeynep H
authors.initials: ZH
authors.lastname: Gümüş
authors.affiliation: Department of Chemical and Biological Engineering, College of Engineering, Koç University, Rumelifeneri Yolu, 34450, Sarıyer, Istanbul, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Erman
mesh_terms: D000494:Allosteric Regulation; D006160:Guanosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras)