Dataset Information

Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups.

ABSTRACT: We report an optimized set of CGenFF parameters that can be used to model small molecules containing acylphosphate and N-phosphonosulfonimidoyl functional groups in combination with the CHARMM force field. Standard CGenFF procedures were followed to obtain bonded interaction parameters, which were validated by geometry optimizations, comparison to the results of calculations at the MP2/6-31+G(d) level of theory, and molecular dynamics simulations. In addition, partial atomic charges were assigned so that the energy of hydrogen bonding of the model compounds with water was correctly reproduced. The availability of these parameters will facilitate computational studies of enzymes that generate acyladenylate intermediates during catalytic turnover. In addition, given that the N-phosphonosulfonimidoyl moiety is a stable transition state analog for the reaction of ammonia with an acyladenylate, the parameters developed in this study should find use in efforts to develop novel and potent inhibitors of various glutamine-dependent amidotransferases that have been validated as drug targets. Topology and parameter files for the model compounds used in this study, which can be combined with other CGenFF parameters in computational studies of more complicated acylphosphates and N-phosphonosulfonimidates are made available.

SUBMITTER: Hegazy L

PROVIDER: S-EPMC3904551 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups.

Hegazy Lamees L Richards Nigel G J NG

Journal of molecular modeling 20131002 11

We report an optimized set of CGenFF parameters that can be used to model small molecules containing acylphosphate and N-phosphonosulfonimidoyl functional groups in combination with the CHARMM force field. Standard CGenFF procedures were followed to obtain bonded interaction parameters, which were validated by geometry optimizations, comparison to the results of calculations at the MP2/6-31+G(d) level of theory, and molecular dynamics simulations. In addition, partial atomic charges were assigne ...[more]

PMID: 24085536

Similar Datasets

Project description:Computational prediction of noncovalent binding free energies with methods based on molecular mechanical force fields has become increasingly routine in drug discovery projects, where they promise to speed the discovery of small molecule ligands to bind targeted proteins with high affinity. Because the reliability of free energy methods still has significant room for improvement, new force fields, or modifications of existing ones, are regularly introduced with the aim of improving the accuracy of molecular simulations. However, comparatively little work has been done to systematically assess how well force fields perform, particularly in relation to the calculation of binding affinities. Hardware advances have made these calculations feasible, but comprehensive force field assessments for protein-ligand sized systems still remain costly. Here, we turn to cyclodextrin host-guest systems, which feature many hallmarks of protein-ligand binding interactions but are generally much more tractable due to their small size. We present absolute binding free energy and enthalpy calculations, using the attach-pull-release (APR) approach, on a set of 43 cyclodextrin-guest pairs for which experimental ITC data are available. The test set comprises both α- and β-cyclodextrin hosts binding a series of small organic guests, each with one of three functional groups: ammonium, alcohol, or carboxylate. Four water models are considered (TIP3P, TIP4Pew, SPC/E, and OPC), along with two partial charge assignment procedures (RESP and AM1-BCC) and two cyclodextrin host force fields. The results suggest a complex set of considerations when choosing a force field for biomolecular simulations. For example, some force field combinations clearly outperform others at the binding enthalpy calculations but not for the binding free energy. Additionally, a force field combination which we expected to be the worst performer gave the most accurate binding free energies - but the least accurate binding enthalpies. The results have implications for the development of improved force fields, and we propose this test set, and potential future elaborations of it, as a powerful validation suite to evaluate new force fields and help guide future force field development.

Dataset Information

Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups.

Publications

Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets