Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

MD simulation based study to understand the role of pre-hydrolysis network in the comparative dynamics of A59G-H-Ras and wild-type H-Ras

The Ras family of proteins plays an important role in cell-proliferation, differentiation, apoptosis, membrane localization and ultimately signal transduction (Downward, 2003). The protein Ras has three isoforms namely H-Ras, K-Ras and N-Ras and belongs to a class of G-proteins. In normal conditions, wild-type Ras regularly cycles between active GTP bound and inactive GDP bound conformations. Also being a GTPase, Ras also possess an intrinsic capability to hydrolyze GTP to GDP and maintain a highly controlled regulation between active and inactive states (Lu et. al, 2016). In gain-of-function mutations of Ras, the intrinsic hydrolysis activity as well GAP-assisted GTP hydrolysis activity is hindered and hence the protein tends to stuck in the permanently active oncogenic state. The oncoprotein Ras is found to be mutated in more than 30% of human cancers (Adjei, 2001). The present work aims to explore the dynamics of the wild-type and mutant A59G-HRas using long-time scale MD simulations, followed by advance MD analytics techniques like MSM based analysis. The in-depth insight into the crucial interactions of wild-type and mutant, especially for the pre-hydrolysis network is reported in the study. Conventional as well feature-based PCA analyses have also been performed to differentiate the wild-type and mutant conformations. The study focuses on the relation between disruption of the crucial pre-hydrolysis network and the oncogenic conformation in the mutant A59G-HRas ensemble. Pivotal roles of residues from SwI, SwII and P-loop has been reported.


    Downward, J. (2003). Targeting RAS signalling pathways in cancer therapy. Nature Reviews Cancer, 3(1), 11.

    Lu, S., Jang, H., Muratcioglu, S., Gursoy, A., Keskin, O., Nussinov, R., & Zhang, J. (2016). Ras conformational ensembles, allostery, and signaling. Chemical reviews, 116(11), 6607-6665.

    Adjei, A. A. (2001). Blocking oncogenic Ras signaling for cancer therapy. Journal of the National Cancer Institute, 93(14), 1062-1074.

Neeru Sharma*,
Uddhavesh B. Sonavane,
Rajendra Joshi


Neeru Sharma is Project Engineer in the HPC-M&BA Group of C-DAC, Pune India, under the supervision of Dr. Uddhavesh Sonawane and Dr. Rajendra Joshi, and will present a short lecture from the platform.

HPC - M&BA Group
Centre for Development of Advanced Computing
Panchawati Road,
Pune 411008, India.

Ph No: 020-25503258,
Email: neerus@cdac.in; rajendra@cdac.in