Investigating the mechanism of action of the synthetic peptide E-MP1 on bacterial and cancer cell membrane models by Molecular Dynamics simulations at equilibrium and constant pH

• Grant number: 24/23092-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: February 28, 2026
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Alexandre Suman de Araujo
• Grantee: Pedro Henrique Favaro Fuzari
• Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
• Associated research grant: 22/07231-7 - Plasticity and functional modulation of intrinsically disordered proteins, AP.TEM

Abstract

This project proposes the investigation of the mechanism of action of the synthetic antimicrobial peptide E-MP1 on bacterial and cancer cell membrane models, using Molecular Dynamics (MD) simulations at equilibrium and constant pH. E-MP1 is a synthetic analogue of the Polybia-MP1 (MP1) peptide, obtained from the immune system of the wasp Polybia paulista, with potential antibiotic and antitumor therapeutic applications. The substitution of aspartic acid residues by glutamic acid in MP1 aims to increase the stability of intra-chain salt bridges and, consequently, the helical structure of the peptide, which influences its lytic action, especially in acidic microenvironments. MD simulations will be performed to compare the adsorption and folding of E-MP1 on model membranes, seeking to understand the influence of the mutation on the peptide-membrane interaction. The formation of intra-chain salt bridges and the conformational space explored by the peptide in the process will also be analyzed. In addition, constant pH simulations (CpHMD) will be employed to investigate the protonation states of E-MP1 in different environments (in solution, in the presence of the lipid bilayer, and adsorbed to the bilayer), comparing the results with those obtained for MP1 in recent publications of our research group. The correlation between the results of the different simulations will be evaluated to determine the therapeutic potential of E-MP1. The obtained results will contribute to the understanding of the mechanisms of action of antimicrobial peptides on cell membranes, with potential application in the development of new therapies for bacterial infections and cancer. If E-MP1 proves promising in the simulations, the primary sequence will be forwarded for experimental testing in collaboration with partner research groups. This project is part of our group's research line, which uses computational methods to study the interaction of peptides with biological membranes, aiming at the development of new therapeutic molecules.