Molecular Mechanics Modeling of the Interactions between the Active Domain of CAP18106–137 and Lipid A

Abstract

AbstractIn this work, a computer search with molecular mechanics calculations is applied to determine the possible low‐energy configurations of two adjacent molecules, CAP18106–137 and lipid A. This computer search is performed by systematically searching the five degrees of freedom that define the relative orientations of the two adjacent molecules. Hydrophilic and hydrophobic units are separated into several small domains along the CAP18106–137 molecule so that it can interact with the lipid A either through the Coulombic interactions with the diphosphoryl head group or through the hydrophobic interactions with the fatty acyl chains. The intermolecular interactions are calculated through the van der Waals and Coulombic interactions. The Coulombic interactions are calculated by using a dielectric constant either with a value of unity ϵ = 1 or with a distance‐dependent dielectric function ϵ(r) = rij. Based on the 400 lowest searched configurations, the intermolecular interactions calculated with ϵ = 1 are found to be about sevenfold lower than those calculated with ϵ(r) = rij. Based on the inspection of the sixteen snapshots of molecular associations, the hydrophobic interactions calculated with ϵ(r) = rij are more favorable than those calculated with ϵ = 1. The high population of the lipid A binding to the CAP 18106–137 molecule is located within the first 19 residues near the N‐terminus of the peptide, as calculated either with e = 1 or with ϵ(r) = rij, by observing the diphosphoryl groups of the lipid A. The orientations of the lipid A with respect to the CAP18106–137 molecule complete an angle of 260°, which appose to the positively charged residues in the N‐terminal half by using the helical wheel projection of the peptide.