Residue interaction networks of K-Ras protein with water molecules identifies the potential role of switch II and P-loop.

The mutant K-Ras with aberrant signaling is the primary cause of several cancers. The proposed study investigated the influence of water molecules in K-Ras crystal structure, where they have a significant function by understanding their residue interaction networks (RINs). We analyzed the RINs of K-Ras with and without water molecules and determined their interaction properties. RINs were developed with the help of StructureViz2 and RINspector; further, the changes in K-Ras backbone flexibility were predicted with the DynaMine. We found that the residues K42, I142, and L159 are the hotspots from water, including the K-Ras-GTP complex with the highest residue centrality analysis (RCA) Z-score. The DynaMine prediction calculated the NMR S value for the frequently mutated positions G12, G13, and Q61 showing a minor shift in flexibility, which make up the P-Loop and switch II of the K-Ras protein. This flexibility shift can account for changes in conformational activity and the protein's GTPase activity, making it difficult to recognize by the effectors and exchange factors. Taken together, our study helps in understanding the functional importance of the water molecules in K-Ras protein and the impact of mutation that modulate the conformational state of the protein.