Antimicrobial peptides (AMPs) are naturally-occurring, short peptides that can show selective toxicity against pathogens including bacteria. Often targeting fundamental, generic bacterial structural features, AMPs force bacteria to adopt costly strategies of resistance making them attractive alternatives to antibiotics. We focus on Buforin II (BF II), a cationic, 21 amino acid AMP whose mechanism of action involves binding to and crossing the bacterial membrane to interact with intracellular targets. Because membrane recognition is an important step, we aim to improve the electrostatic component of BF II--membrane interaction using computational design, with an ultimate goal to understand more precisely how membrane affinity relates to potency. Past work suggests that increasing the overall monopole of BF II through arginine substitution improves electrostatic interaction between the peptide and a different negatively-charged target, DNA. However, the amount of improvement is position-dependent. To begin our design for this system, we generate a conformational ensemble of the peptide/membrane system with molecular dynamics (MD) simulations of wild-type BF II and membrane. Then, as a first, coarse model to efficiently narrow the set of potential substitution positions, we carry out partial charge optimization on snapshots from the WT simulation to select promising peptide mutants for future MD simulations. Partial charge optimization employs a continuum electrostatics model to determine a binding partner’s hypothetical charge distribution that would optimize affinity. Here, we use it to estimate which BF II residues should be converted to a positive charge in order to cause the greatest increase in binding affinity. This project may provide the basis for understanding the mechanism of BF II and related AMPs and for increasing its potency as an antimicrobial agent.

Computational design of Buforin-2-based antimicrobial peptides with improved electrostatic interactions with the cell membrane

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.