Quantitative comparison of the structural differences between NRAS and its mutations by well-tempered metadynamics simulations

The NRAS-mutant subset of melanoma is one of the most aggressive and lethal types associated with poor overall survival. Unfortunately, a low understanding of the NRAS-mutant dynamic behavior has lead to the lack of clinically approved therapeutic agents able to directly target NRAS oncogenes. In this work, accurate local structures of NRAS and its mutants have been fully explored through the corresponding free energy surfaces obtained by microsecond scale well-tempered metadynamics simulations. Free energy calculations are crucial to reveal the precise mechanisms of Q61 mutations at the atomic level. Considering specific atom-atom distances d and angles{phi} as appropriate reaction coordinates we have obtained free energy surfaces revealing local and global minima together with their main transitions states, unvealing the mechanisms of abnormal NRAS activation from atomic-level and quantitatively analyzing the corresponding stable states. This will help to advance in our understanding of the basic mechanisms of NRAS mutations, offering new opportunities for the design of potential inhibitors.