Most Probable Druggable Pockets in Mutant p53-Arg175His Clusters Extracted from Gaussian Accelerated Molecular Dynamics Simulations

p53, a tumor suppressor protein, is essential for preventing cancer development. Enhancing our understanding of the human p53 function and its modifications in carcinogenesis will aid in developing more highly effective strategies for cancer prevention and treatment. In this study, we have modeled five human p53 forms, namely, inactive, distal-active, proximal-active, distal-Arg175His mutant, and proximal-Arg175His mutant forms. These forms have been investigated using Gaussian accelerated molecular dynamics (GaMD) simulations in OPC water model at physiological temperature and pH. Our observations, obtained throughout 200 ns of production run, are in good agreement with the relevant results in the classical molecular dynamics (MD) studies. Therefore, GaMD method is more economic and efficient method than the classical MD method for studying biomolecular systems. The featured dynamics of the five human p53-DBD forms include noticeable conformational changes of L1 and α 1 – β 5 loops as well as β 6 – β 7 and β 7 – β 8 turns. We have identified two clusters that represent two distinct conformational states in each p53-DBD form. The free-energy profiles of these clusters demonstrate the flexibility of the protein to undergo a conformational transition between the two clusters. We have predicted two out of seven possible druggability pockets on the clusters of the Arg175His forms. These two druggability pockets are near the mutation site and are expected to be actual pockets, which will be helpful for the compound clinical progression studies.