Elucidating conformational dynamics of GDP/GTP-KRAS complexes caused by mutations from the switch domain I through Gaussian accelerated molecular dynamics simulations

The conformational dynamics of the switch domain 1 (SWI) of KRAS plays an important role in binding of KRAS to effectors. Clarifying molecular mechanism of the effect of mutations in SWI on conformational dynamics of KRAS is of significance for understanding the function of KRAS. Gaussian accelerated molecular dynamics (GaMD) simulations were performed on GDP/GTP-wild type (WT) and mutated KRAS to investigate the influences of two mutations P34R and T35S in SWI on conformational dynamics of KRAS. The analyses of free energy landscapes (FELs) reveal that P34R and T35S induce looser switch regions than WT KRAS, moreover the switch regions in GTP-P34R and T35S KRAS are wider than those in GDP-P34R and T35S one. Meanwhile, P34R and T35S highly affect structural flexibility of SWI and the loop L3, which disturbs binding of KRAS to effectors or regulators and the allosteric regulation of KRAS activity. In addition, the analyses of interaction networks suggest that P34R and T35S weaken hydrogen bonding interactions (HBIs) of SWI with GDP/GTP and influence electrostatic interactions (EIs) of SWI with magnesium ion (Mg²⁺), which also implies the effects of P34R and T35S on binding of KRAS to effectors or regulators and KRAS activity. This work is expected to contribute theoretical help and dynamics information for further understanding the function of KRAS and drug design toward the RAS proteins.