Mechanism of Antimicrobial Peptide Binding to Membrane-mimetic Systems: Insight from Molecular Dynamics Simulations

Abstract

"The focus of the Ph.D. thesis was to understand the mechanism of cationic antimicrobial peptide (7 and 14 amino acid residue long) binding to membrane-mimetic systems (micelle and bilayer) using classical molecular dynamics free energy simulations. The peptides were modeled and subjected to conventional classical MD simulations in the presence and absence of micelle/bilayer [micelles: SDS/DPC and bilayers: (DOPE:DOPG and POPE:POPG)/POPC as bacterial/mammalian membrane-mimic]. The structures of the free peptides in water and in complex with the membrane-mimetic systems were predicted from the conventional MD simulations and verified by our experimental collaborators. The MD structures were used as a template for estimating the energetics of peptide: micelle/bilayer binding (ΔGbind; absolute binding affinity and ΔΔG; Binding free energy difference between two peptides to the membrane-mimetic system) by employing various popular methods: Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), Steered Molecular Dynamics (SMD), Umbrella Sampling (US), and Alchemical free energy simulations (FEP, TI, BAR). The simulations of peptide binding to the simplest membrane-mimetic systems provide insight into the kinetics and establish a direct link between the calculated energetics and molecular structures."