In silico design and optimization of anticancer peptide to inhibit mutant k-ras

Abstract

Cancer is one of the major health concerns worldwide, and there is an ongoing effort to find novel treatment approaches. RAS Proteins play a pivotal role in the proliferation pathways, and their mutations can lead to persistent RAS activation and cancerous cells. In this regard, several peptides have been designed and studied. However, there was no clinically approved peptide for K-Ras inhibition. Objective: In this study, two K-Ras binding template peptides, KRpep2d and Sos-αH motif, were used to mutate and the selected peptides were further studied and analyzed by MD simulation to propose a promising K-Ras inhibitory peptide. Methods: FoldX program was used to mutate and screened the KRpep2d and Sos αH motif peptides.The selected peptides were named M79,ps939,ps944 and psdm.MD simulations of KRAS variants in the free and complex form with all the selected and original peptides were carried out via "GROMACS" software. Supplementary analyses were performed after the simulation of systems. The distance variations of residues in different systems, were conducted to define conformational changes. Moreover, the affinities of peptides and the nucleotide to K-Ras were measured by the "Umbrella Sampling" method. Also, residue interactions and β2-strand length of K-Ras variants were calculated by "LigPlot plus" software, DSSP plugin of "GROMACS" software, respectively. System snapshots were represented by "CHIMERA UCSF"software.

Results: Comprehending the analyzed data, we suggested, it could be two different approaches to select the best peptide candidates for K-Ras inhibition, including 1) Based on Best peptide affinity for K-Ras GDP form and switchI/SwitchII distance reduction 2)Best peptide affinity for KRas-GCP form and their β2-strand size reduction. Based on approaches, ps939 and ps944 showed higher binding energy to G12C-GDP and G12C-GCP. They caused a dramatic change in switchI/SwitchII distance which shows the reduction of active K-Ras. Also, they led to β2-strand size reduction, which indicates these peptides' capability in the decreasing of the K-Ras activity. Conclusion: We suggested ps939 and ps944 promising K-Ras-G12C inhibitory peptides.