Beta‐hairpin restraint potentials for calculations of potentials of mean force as a function of beta‐hairpin tilt, rotation, and distance

We have developed a set of restraint potentials for beta-hairpin tilt relative to the membrane normal, beta-hairpin rotation around the beta-hairpin axis, and hairpin-hairpin distance. Such restraint potentials enable us to characterize the molecular basis of specific beta-hairpin tilt and rotation in membranes and hairpin-hairpin interactions at the atomic level by sampling their conformational space along these degrees of freedom, i.e., reaction coordinates, during molecular dynamics simulations. We illustrate the efficacy of the beta-hairpin restraint potentials by calculating the potentials of mean force (PMFs) as a function of tilt and rotation angles of protegrin-1 (PG-1), a beta-hairpin antimicrobial peptide, in an implicit membrane model. The peptide association in the membrane is also examined by calculating the PMFs as a function of distance between two PG-1 peptides in various dimer interfaces. These novel restraint potentials are found to perform well in each of these cases and are expected to be a useful means to study the microscopic driving forces of insertion, tilting, and rotation of beta-hairpin peptides in membranes as well as their association in aqueous solvent or membrane environments particularly when combined with explicit solvent models.