Empirical corrections and pair interaction energies in the fragment molecular orbital method

The energy and analytic gradient are developed for FMO combined with the Hartree-Fock method augmented with three empirical corrections (HF-3c). The auxiliary basis set approach to FMO is extended to perform pair interaction energy decomposition analysis. The FMO accuracy is evaluated for several typical systems including 3 proteins. Pair interaction energies computed with different approaches in FMO are compared for a water cluster and protein-ligand complexes.Comment: Revised version accepted in Chemical Physics Letter

A computational method for the systematic screening of reaction barriers in enzymes:searching for Bacillus circulans xylanase mutants with greater activity towards a synthetic substrate

We present a semi-empirical (PM6-based) computational method for systematically estimating the effect of all possible single mutants, within a certain radius of the active site, on the barrier height of an enzymatic reaction. The intent of this method is not a quantitative prediction of the barrier heights, but rather to identify promising mutants for further computational or experimental study. The method is applied to identify promising single and double mutants of Bacillus circulans xylanase (BCX) with increased hydrolytic activity for the artificial substrate ortho-nitrophenyl β-xylobioside (ONPX2). The estimated reaction barrier for wild-type (WT) BCX is 18.5 kcal/mol, which is in good agreement with the experimental activation free energy value of 17.0 kcal/mol extracted from the observed kcat using transition state theory (Joshi et al., 2001). The PM6 reaction profiles for eight single point mutations are recomputed using FMO-MP2/PCM/6-31G(d) single points. PM6 predicts an increase in barrier height for all eight mutants while FMO predicts an increase for six of the eight mutants. Both methods predict that the largest change in barrier occurs for N35F, where PM6 and FMO predict a 9.0 and 15.8 kcal/mol increase, respectively. We thus conclude that PM6 is sufficiently accurate to identify promising mutants for further study. We prepared a set of all theoretically possible (342) single mutants in which every amino acid of the active site (except for the catalytically active residues E78 and E172) was mutated to every other amino acid. Based on results from the single mutants we construct a set of 111 double mutants consisting of all possible pairs of single mutants with the lowest barrier for a particular position and compute their reaction profile. None of the mutants have, to our knowledge, been prepared experimentally and therefore present experimentally testable predictions

In silico prediction of mutant HIV-1 proteases cleaving a target sequence

HIV-1 protease represents an appealing system for directed enzyme re-design, since it has various different endogenous targets, a relatively simple structure and it is well studied. Recently Chaudhury and Gray (Structure (2009) 17: 1636 -- 1648) published a computational algorithm to discern the specificity determining residues of HIV-1 protease. In this paper we present two computational tools aimed at re-designing HIV-1 protease, derived from the algorithm of Chaudhuri and Gray. First, we present an energy-only based methodology to discriminate cleavable and non cleavable peptides for HIV-1 proteases, both wild type and mutant. Secondly, we show an algorithm we developed to predict mutant HIV-1 proteases capable of cleaving a new target substrate peptide, different from the natural targets of HIV-1 protease. The obtained in silico mutant enzymes were analyzed in terms of cleavability and specificity towards the target peptide using the energy-only methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence

A needed response: Fragment molecular orbital analytic gradients

Ab initio quantum chemistry seeks to describe and elucidate chemical species and processes using quantum mechanics. For dynamical chemical processes, molecular dynamics (MD), where the atoms of a chemical system move according to Newton\u27s laws of motion, is frequently used. MD calculations have historically used classical mechanics rather than quantum mechanics to describe the evolution of a chemical system. The use of classical mechanics with MD has proven to be a great success, but classical MD has deficiencies, since quantum mechanics must be used to describe important chemical phenomena such as bond breaking or excited states accurately. With the increase of computer power over the past half-century, ab initio MD (AIMD) methods that describe a chemical system using quantum mechanics have been developed to eliminate the deficiencies of classical MD. Unfortunately, the application of AIMD is limited to small systems and short time scales since standard quantum chemical methods exhibit non-linear scaling with system size. More recently, new approaches have circumvented the non-linear scaling of quantum chemical methods by exploiting the fact that most chemical interactions are local and therefore distant interactions can be approximated or even ignored. Other methods obtain quantum mechanical accuracy at a cost associated with classical mechanics by deriving a classical force field directly from ab initio calculations. Individually and in combination, methods that eliminate the non-linear scaling of standard ab initio methods have the potential to extend the reach of AIMD to larger systems such as surfaces, molecular clusters, bulk liquids, and proteins