All-Hydrocarbon Staples and Their Effect over Peptide Conformation under Different Force Fields.

Abstract

Olefinic staples enhance α-helical content and conformational stability in peptides, maintaining a structural scaffold that allows the emulation of specific regions of protein surfaces for therapeutical purposes. The ability to anticipate the efficacy of adding a staple to a peptide through computational simulations may contribute to lowering the costs associated with rational drug design. We evaluated the capabilities of different force fields to reproduce the effect of all-hydrocarbon staples in molecular dynamics simulations. Using the AMBER99SB-ILDN, CHARMM36, and GROMOS54A7 force fields and two distinct initial conformations, we compared our results to experimentally obtained circular dichroism data. The GROMOS54A7 united-atom force field seems to be more accurate compared with all-atom force fields, despite being unable to reproduce the effect of the staple in some of the simulated systems. With further force field enhancements, MD simulations may be used to anticipate conformational effects of all-hydrocarbon staples in peptides.