Biomolecular Simulations of Halogen Bonds with a GROMOS Force Field

Halogen
bonds (XBs) are non-covalent interactions in which halogens
(X), acting as electrophiles, interact with Lewis bases. XBs are able
to mediate protein–ligand recognition and therefore play an
important role in rational drug design. In this context, the development
of molecular modeling tools that can tackle XBs is paramount. XBs
are predominantly explained by the existence of a positive region
on the electrostatic potential of X named the σ-hole. Typically,
with molecular mechanics force fields, this region is modeled using
a charged extra point (EP) linked to X along the R–X covalent
bond axis. In this work, we developed the first EP-based strategy
for GROMOS force fields (specifically GROMOS 54A7) using bacteriophage
T4 lysozyme in complex with both iodobenzene and iodopentafluorobenzene
as a prototype system. Several EP parametrization schemes were tested
by adding a virtual interaction site to ligand topologies retrieved
from the Automated Topology Builder (ATB) and Repository. Contrary
to previous approaches using other force fields, our analysis is based
on the capability of each parametrization scheme to sample XBs during
MD simulations. Our results indicate that the implementation of an
EP at a distance from iodine corresponding to Rmin provides a good qualitative description of XBs in MD simulations,
supporting the compatibility of our approach with the GROMOS 54A7
force field.