Normal Mode Analysis of KRas4B Reveals Partner Specific Dynamics

Meryem Eren, Nurcan Tuncbag, Hyunbum Jang, Ruth Nussinov, Attila Gursoy, Ozlem Keskin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)5210-5221
Number of pages12
JournalJournal of Physical Chemistry B
Issue number20
StatePublished - 27 May 2021


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