Molecular simulations of DD‐peptidase, a model ß‐lactam‐binding protein: Synergy between X‐ray crystallography and computational chemistry

Abstract

Using computer model building, the three-dimensional structure of an enzyme from Streptomyces R61 that is inhibited by p-lactam antibiotics has been constructed starting from incomplete X-ray crystallographic data for this 37.4 kDa protein. The so-called DD-peptidase catalyzes transpeptidation and hydrolysis of peptides terminating in D-Ala-D-Ala and is a model for bacterial transpeptidases and carboxypeptidases essential in the biosynthesis of the peptidoglycan layer of the cell wall. The structure, which was completed with the SYBYL molecular modeling package, has been refined by energy minimization and molecular dynamics using Quanta/CHARMm software. A simulation of 105 ps was run with waters of solvation in the active site. From these computations, the interatomic distances between the active serine and key residues around the active site were determined. Inadequacies at reproducing geometric details of the p-lactam ring of a cephalosporin are pointed out which are typical of most commercially available force fields.

Conformational analysis of bacterial cell wall peptides indicates how particular conformations have influenced the evolution of penicillin‐binding proteins, β‐lactam antibiotics and antibiotic resistance mechanisms

“…Default SYBYL atom types were applied except for protonated amino groups, carboxylate oxygens and the lactam nitrogen, which were assigned N4, Oco2 and Nam atom types, respectively (Boyd et al, 1991;. Search runs of 1000 iterations were routinely used, to provide representative conformer populations of the constrained b-lactam starting structures.…”

Molecular Modeling of Geometries, Charge Distributions, and Binding Energies of Small, Druglike Molecules Containing Nitrogen Heterocycles and Exocyclic Amino Groups in the Gas Phase and in Aqueous Solution

“…Continuing advances in molecular modeling and computational chemistry have greatly facilitated the structure-based design of small-molecule inhibitors of proteins. − Although molecular mechanics (MM) force fields − can model protein structure, they often lack parameters that accurately represent the heteroatomic groups present in pharmaceuticals. − Density functional theory (DFT) and wave function theory (WFT) do not require new parameters for each type of atom; however, current technology still limits the calculations to smaller molecules and exploratory studies on larger systems. Two viable approaches for simulating a protein bound to a druglike inhibitor are to obtain MM parameters for force fields that yield accurate molecular geometries and partial charges or to find a suitable level of combined QM/MM theory − in which a critical or active region of the system is treated by quantum mechanics (QM) and the surrounding areas by MM.…”