KRas4B Conformational Differences are Highlighted by Computational Analysis with GNM-ANM

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2022-10

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Eren, Meryem
Tunçbağ, Nurcan
Nussinov, Ruth
Jang, Hyunbum
Gursoy, Attila
Keskin, Özlem

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Ras GTPase has critical functions in cellular signaling. Rasrelated human cancers form as a result of disrupted interactions with its regulators and effectors. Our aim is to aid in targeting these disrupted mechanisms by understanding the distinct dynamics of Ras protein−protein interactions. We performed normal mode analysis (NMA) of KRas4B in monomeric and heterodimeric conformational states to reveal partner-specific dynamics of the protein. Gaussian network models (GNM) and anisotropic network models (ANM) were applied in performing NMA. These coarse-grained models allow us to estimate residue fluctuations around the proteins’ native state and provide valuable information regarding protein’s global and local motions. According to GNM analysis, the known KRas4B lobes further divide into subdomains following binding to its partners. Additionally, KRas4B interactions with various partners specifically inhibit the flexibility of distant residues in the allosteric lobe, as well as the protein binding sites. The results of the ANM study showed that the intrinsic residue fluctuations of KRas4B can drive the conformational changes. Our NMA results were validated by network analysis measures like node centrality and betweenness metrics. Overall, these aid in the comprehension of partner-specific KRas4B dynamics, which may be applied for therapeutic targeting.

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https://hibit2022.ims.metu.edu.tr
https://hdl.handle.net/11511/101348

Conference Name

The International Symposium on Health Informatics and Bioinformatics

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Graduate School of Informatics, Conference / Seminar

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Citation Formats

M. Eren, N. Tunçbağ, R. Nussinov, H. Jang, A. Gursoy, and Ö. Keskin, “KRas4B Conformational Differences are Highlighted by Computational Analysis with GNM-ANM,” Erdemli, Mersin, TÜRKİYE, 2022, p. 3090, Accessed: 00, 2023. [Online]. Available: https://hibit2022.ims.metu.edu.tr.