Issue 8, 2022

Predicting the conformational variability of oncogenic GTP-bound G12D mutated KRas-4B proteins at zwitterionic model cell membranes

Abstract

KRas proteins are the largest family of mutated Ras isoforms, participating in a wide variety of cancers. Due to their importance, large effort is being carried out on drug development by small-molecule inhibitors. However, understanding protein conformational variability remains a challenge in drug discovery. In the case of the Ras family, their multiple conformational states can affect the binding of potential drug inhibitors. To overcome this challenge, we propose a computational framework based on combined all-atom Molecular Dynamics and Metadynamics simulations in order to accurately access conformational variants of the target protein. We tested the methodology using a G12D mutated GTP bound oncogenic KRas-4B protein located at the interface of a DOPC/DOPS/cholesterol model anionic cell membrane. Two main orientations of KRas-4B at the anionic membrane have been determined. The corresponding torsional angles are taken as reliable reaction coordinates so that free-energy landscapes are obtained by well-tempered metadynamics simulations, revealing local and global minima of the free-energy hypersurface and unveiling reactive paths of the system between the two preferential orientations. We have observed that GTP-binding to KRas-4B has huge influence on the stabilisation of the protein and it can potentially help to open Switch I/II druggable pockets, lowering energy barriers between stable states and resulting in cumulative conformers of KRas-4B. This may highlight new opportunities for targeting the unique meta-stable states through the design of new efficient drugs.

Graphical abstract: Predicting the conformational variability of oncogenic GTP-bound G12D mutated KRas-4B proteins at zwitterionic model cell membranes

Supplementary files

Article information

Article type
Paper
Submitted
18 Nov 2021
Accepted
06 Feb 2022
First published
07 Feb 2022

Nanoscale, 2022,14, 3148-3158

Predicting the conformational variability of oncogenic GTP-bound G12D mutated KRas-4B proteins at zwitterionic model cell membranes

H. Lu and J. Martí, Nanoscale, 2022, 14, 3148 DOI: 10.1039/D1NR07622A

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