Studies of molecular modeling on drug design of Listeria monocytogenes internalin B β-sheet

Abstract

Internalin B (InlB) is an extracellular virulence factor of the bacterium Listeria monocytogenes, (italic) and it contains seven leucine rich repeats (LRRs) which is composed of seven β-strands aligned to form a continuous β–sheet. This β–sheet which is composed of a linear arrangement of five exposed aromatic amino acids is a hot–spot for host receptor (Met) binding and this is the goal of our studies. At first glance, the molecule were optimized with 6 to 31G (d,p) basis set in the gas phase at the Hartree–Fock (HF) level of theory. To simulate the solvent effect, the HF optimized parameters were used as initial input for subsequent HF/self–consistent reaction field (SCRF) calculations in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity, as well as the hydrogen bond donor and acceptor strength, implementing 6 to 31G (d,p) atomic basis set. For deeper investigations of β–sheet folding, thermodynamic signatures of this biomolecule as an island of cooperatively–ordered hydrogen–bonded network by calculating Gibbs free energy and enthalpy were determined. Four different temperatures that this bacterium may encounter in the environment, and in cold-blooded animals or warm-blooded hosts in three solvent media were used. Then, NMR studies was carried out on the basis of gauge-including atomic orbital (GIAO) method at HF/6–31G (d,p) level of theory, to gain more insight to solvent effects on aromatic amino acids ¹⁵N and ¹⁷O atoms shielding in order to probe InlB–Met (ligand–protein) binding via clarifying of chemical shift mapping and dynamics.

Key words: Internalin B, β–sheet (un) folding, thermodynamics, solvent effect, nuclear magnetic resonance.