A Database of Force-Field Parameters, Dynamics, and Properties of Antimicrobial Compounds

Abstract

We present an on-line database of all-atom force-field parameters and molecular properties of compounds with antimicrobial activity (mostly antibiotics and some beta-lactamase inhibitors). For each compound, we provide the General Amber Force Field parameters for the major species at physiological pH, together with an analysis of properties of interest as extracted from µs-long molecular dynamics simulations in explicit water solution. The properties include number and population of structural clusters, molecular flexibility, hydrophobic and hydrophilic molecular surfaces, the statistics of intraand inter-molecular H-bonds, as well as structural and dynamical properties of solvent molecules within first and second solvation shells. In addition, the database contains several key molecular parameters, such as energy of the frontier molecular orbitals, vibrational properties, rotational constants, atomic partial charges and electric dipole moment, computed by Density Functional Theory. The present database (to our knowledge the first extensive one including dynamical properties) is part of a wider project aiming to build-up a database containing structural, physico-chemical and dynamical properties of medicinal compounds using different force-field parameters with increasing level of complexity and reliability. The database is freely accessible at

Extracting Conformational Ensembles of Small Molecules from Molecular Dynamics Simulations: Ampicillin as a Test Case

“…We additionally generated the General AMBER Force Field (GAFF) parameters [42] for each major tautomer in the pH range 2-14 and performed µs-long MD simulations for the species bearing net charges −2, −1 and +1. The parameters and the molecular descriptors extracted from both quantum-mechanics and MD simulations are available online [27]. Our results indicate that the conformational statistics extracted from plain MD simulations is: (i) consistent with that obtained from REMD simulations; and (ii) performs slightly better than some widely-used conformer generation tools when considering both the abilities to generate high-diversity conformational ensembles and to reproduce experimentally the available structures.…”

“…The 3D structure of each microspecies has been subsequently used to perform density functional theory (DFT) calculations [46] with the GAUSSIAN09 package [47]. As already done in our systematic investigation [27], we employed the hybrid B3LYP functional [48,49] and the 6-31G basis-set [50]. The combination B3LYP/6-31G is a good compromise between accuracy and computational cost [51,52].…”

“…The combination B3LYP/6-31G is a good compromise between accuracy and computational cost [51,52]. All GAUSSIAN09 calculations were performed using the same settings adopted in our previous study [27]. For each major tautomer in the pH range 2-14, we used the DFT optimized geometry to compute logP values with XLOGP3 [53] and polar/non-polar molecular surfaces through the PLATINUM web interface [54].…”

“…Recently, in the framework of the TRANSLOCATION consortium [26], we have started building a large database of antimicrobial compounds containing all-atom FF parameters, as well as physico-chemical descriptors derived from both quantum-mechanics and µs-long MD simulations [27]. Our database, freely accessible online, is to our knowledge the first extensive one including dynamical properties for a large set of compounds.…”

“…In the following, we will simply refer to the molecule using the corresponding Protein Data Bank chemical component identifier AMP. Thus, considering the AMP neutral zwitterionic form, the most populated one at physiological pH 7.4, we first compared our conformational landscape extracted from plain MD simulations [27] with those obtained by means of: (i) Replica Exchange MD (REMD) [39]; and (ii) some freely-available conformer generation tools widely used in computer-aided drug-design [41]. We additionally generated the General AMBER Force Field (GAFF) parameters [42] for each major tautomer in the pH range 2-14 and performed µs-long MD simulations for the species bearing net charges −2, −1 and +1.…”