The role of conserved waters in conformational transitions of Q61H K-ras.

PLoS Computational Biology
Priyanka PrakashAlemayehu A Gorfe

Abstract

To investigate the stability and functional role of long-residence water molecules in the Q61H variant of the signaling protein K-ras, we analyzed all available Ras crystal structures and conformers derived from a series of independent explicit solvent molecular dynamics (MD) simulations totaling 1.76 µs. We show that the protein samples a different region of phase space in the presence and absence of several crystallographically conserved and buried water molecules. The dynamics of these waters is coupled with the local as well as the global motions of the protein, in contrast to less buried waters whose exchange with bulk is only loosely coupled with the motion of loops in their vicinity. Aided by two novel reaction coordinates involving the distance (d) between the C(α) atoms of G60 at switch 2 and G10 at the P-loop and the N-C(α)-C-O dihedral (ξ) of G60, we further show that three water molecules located in lobe1, at the interface between the lobes and at lobe2, are involved in the relative motion of residues at the two lobes of Q61H K-ras. Moreover, a d/ξ plot classifies the available Ras x-ray structures and MD-derived K-ras conformers into active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free conformati...Continue Reading

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Citations

Mar 5, 2013·Annual Review of Biophysics·Ruth NussinovBuyong Ma
Jun 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Harrison J HockerAlemayehu A Gorfe
Jan 14, 2016·The Journal of Physical Chemistry. B·Mayukh ChakrabartiRuth Nussinov
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Apr 8, 2015·Proteins·Abhijeet Kapoor, Alex Travesset
Aug 3, 2013·Biochimica Et Biophysica Acta·Priyanka Prakash, Alemayehu A Gorfe
Jan 1, 2014·Molecular Simulation·Priyanka Prakash, Alemayehu A Gorfe
Oct 28, 2015·PLoS Computational Biology·Priyanka PrakashAlemayehu A Gorfe
Mar 3, 2017·Journal of Chemical Theory and Computation·Abdallah Sayyed-Ahmad, Alemayehu A Gorfe
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May 13, 2017·Proteins·Abdallah Sayyed-AhmadAlemayehu A Gorfe
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Oct 16, 2014·The Journal of Physical Chemistry. B·Obaidur RahamanFabio Sterpone
Sep 2, 2017·Journal of the American Chemical Society·Suparna Sarkar-BanerjeeAlemayehu A Gorfe

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Methods Mentioned

BETA
neutron scattering
nucleotide exchange
PCA

Software Mentioned

PCA
SHAKE
NAMD

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