Dynamic Coupling and Entropy Changes in KRAS G12D Mutation: Insights into Molecular Flexibility, Allostery and Function

Abstract

The oncogenic G12D mutation in KRAS is a major driver of cancer progression, yet the complete mechanism by which this mutation alters protein dynamics and function remains incompletely understood. Here, we investigate how the G12D mutation alters KRASs conformational landscape and residue-residue interactions using molecular dynamics simulations coupled with entropy calculations and mutual information (MI) analysis. We demonstrate that the mutation increases local entropy at key functional residues (D12, Y32, G60, and Q61), and introduces new peaks to the Ramachandran angles, disrupting the precise structural alignment necessary for GTP hydrolysis. Notably, while individual residue entropy increases, joint entropy analysis shows a complex reorganization pattern. MI analysis identifies enhanced dynamic coupling between distant residues, suggesting that the mutation establishes new long-range interactions that stabilize the active state. These findings show how G12D mutation redefines KRASs dynamic network, leading to persistent activation through enhanced residue coupling rather than mere local disruption. Our results suggest novel therapeutic strategies focused on modulating protein dynamics rather than targeting specific binding sites, potentially offering new approaches to combat KRAS-driven cancers. HighlightsO_LIThe G12D mutation increases entropy and mutual information between residue pairs, resulting in more correlated motions due to enhanced flexibility. C_LIO_LICharacteristic features of local and long-range allostery in wild-type (WT) and G12D KRAS are determined using structural proximity and mutual information analysis. C_LIO_LIThe dynamics of KRAS interactions with its natural ligand atoms and the coordination of bridging water molecules provide insights into the changes induced by the G12D mutation. C_LI