Optimization of binding affinity and stability of anti- mutant KRAS peptides using Molecular Dynamics Simulation

Abstract

Background: RAS proteins play a central role in proliferation pathways, and mutations in them can lead to sustained RAS activation and developing cancer cells. Thera are some limitations regarding the inhibition of mutant RAS proteins by small molecules. Therefore, peptides are promising therapeutic targets for mutant RAS suppression. However, optimizing the stability and binding affinity of peptides is necessary. Objective: we aimed to optimize peptides with KRAS inhibition capability to achieve more potent and stable therapeutic candidates. Methods: In this study, an optimized peptide sequence, derived from Sos-αH motif in SOS-KRAS interaction, was used to D-amino acid mutation to increase the stability. Chimera software was used to mutate each L-amino acid into its D-amino acid form. MD simulations of KRAS-D peptide complexes were performed using “GROMACS” software by including and the D-amino acids topology. After simulating the system, supplementary analyzes were performed. We measured the affinity of peptides to KRAS using the umbrella sampling method. Furthermore, the hydrogen binding and β2 chain lengths of KRAS variants were calculated. The system snapshot was rendered by the software “CHIMERA UCSF”.Results: There are different approaches to select the best peptide candidates for K-Ras inhibition for example one is Based on the best peptide affinity to wild type/mutant KRAS proteins. Another way is the mechanistic reduction of β2 sheet size of wild type/mutant KRAS proteins. The D-sos peptide type D2E showed higher binding energies towards G12C-GCP and G12D-GCP and also acceptable binding threshold with the lowest binding affinity energy with K-ras wild type. Furthermore, they resulted in a decrease in the size of the β2 chain, indicating the ability of these peptides to reduce K-Ras activity.Conclusion: We suggested peptide type D2E as a promising mutant KRAS inhibitory peptides.