Open AccessNormal Mode Analysis of KRas4B Reveals Partner Specific Dynamics
Author(s) -
Meryem Eren,
Nurcan Tunçbağ,
Hyunbum Jang,
Ruth Nussinov,
Attila Gürsoy,
Özlem Keskin
Publication year - 2021
Publication title -
the journal of physical chemistry. b
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.864
H-Index - 392
eISSN - 1520-6106
pISSN - 1520-5207
DOI - 10.1021/acs.jpcb.1c00891
Subject(s) - dynamics (music) , mode (computer interface) , computer science , physics , human–computer interaction , acoustics
Ras GTPase interacts with its regulators and downstream effectors for its critical function in cellular signaling. Targeting the disrupted mechanisms in Ras-related human cancers requires understanding the distinct dynamics of these protein-protein interactions. We performed normal mode analysis (NMA) of KRas4B in wild-type or mutant monomeric and neurofibromin-1 (NF1), Son of Sevenless 1 (SOS1) or Raf-1 bound dimeric conformational states to reveal partner-specific dynamics of the protein. Gaussian network model (GNM) analysis showed that the known KRas4B lobes further partition into subdomains upon binding to its partners. Furthermore, KRas4B interactions with different partners suppress the flexibility in not only their binding sites but also distant residues in the allosteric lobe in a partner-specific way. The conformational changes can be driven by intrinsic residue fluctuations of the open state KRas4B-GDP, as we illustrated with anisotropic network model (ANM) analysis. The allosteric paths connecting the nucleotide binding residues to the allosteric site at α3-L7 portray differences in the inactive and active states. These findings help in understanding the partner-specific KRas4B dynamics, which could be utilized for therapeutic targeting.