Atomistic Simulations of Wimley–White Pentapeptides: Sampling of Structure and Dynamics in Solution

Wimley?White pentapeptides (Ac-WLXLL) can be used as a model system to study lipid?protein interactions as they bind to lipid/water interfaces, like many antimicrobial peptides, and thermodynamic experimental data on their interactions with lipids are available, making them useful for both force field and method testing and development. Here we present a detailed simulation study of Wimley?White (WW) peptides in bulk water to investigate sampling, conformations, and differences due to the different X residue with an eye to future simulations at the lipid/water interface where sampling problems so far have hindered free energy calculations to reproduce the experimental thermodynamic data. We investigate the conformational preferences and slowest relaxation time of WW peptides in bulk water by building Markov State Models (MSM) from Molecular Dynamics (MD) simulation data. We show that clustering based on binning of backbone ?, ? dihedrals in combination with the community detection algorithm of Blondel et al. provides a quick way of building MSM from large data sets. Our results show that in some cases, implied times even in these small peptides range from 224 to 547 ns. The implications of these slow transitions on determining the potential of mean force profiles of peptide interactions with a lipid bilayer are discussed.