GMXPBSA 2.0: A GROMACS tool to perform MM/PBSA and computational alanine scanning

Abstract

GMXPBSA 2.0 is a user-friendly suite of Bash/Perl scripts for streamlining MM/PBSA calculations on structural ensembles derived from GROMACS trajectories, to automatically calculate binding free energies for protein–protein or ligand–protein complexes. GMXPBSA 2.0 is flexible and can easily be customized to specific needs. Additionally, it performs computational alanine scanning (CAS) to study the effects of ligand and/or receptor alanine mutations on the free energy of binding. Calculations require only for protein–protein or protein–ligand MD simulations. GMXPBSA 2.0 performs different comparative analysis, including a posteriori generation of alanine mutants of the wild-type complex, calculation of the binding free energy values of the mutant complexes and comparison of the results with the wild-type system. Moreover, it compares the binding free energy of different complexes trajectories, allowing the study the effects of non-alanine mutations, post-translational modifications or unnatural amino acids on the binding free energy of the system under investigation. Finally, it can calculate and rank relative affinity to the same receptor utilizing MD simulations of proteins in complex with different ligands. In order to dissect the different MM/PBSA energy contributions, including molecular mechanic (MM), electrostatic contribution to solvation (PB) and nonpolar contribution to solvation (SA), the tool combines two freely available programs: the MD simulations software GROMACS and the Poisson–Boltzmann equation solver APBS. All the calculations can be performed in single or distributed automatic fashion on a cluster facility in order to increase the calculation by dividing frames across the available processors. The program is freely available under the GPL license. Program summaryProgram title: GMXPBSA 2.0Catalogue identifier: AETQ_v1_0Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AETQ_v1_0.htmlProgram obtainable from: CPC Program Library, Queen’s University, Belfast, N. IrelandLicensing provisions: GNU General Public License, version 3No. of lines in distributed program, including test data, etc.: 185937No. of bytes in distributed program, including test data, etc.: 7074217Distribution format: tar.gzProgramming language: Bash, Perl.Computer: Any computer.Operating system: Linux, Unix OS.RAM: ∼2 GBClassification: 3.External routines: APBS (http://www.Poissonboltzmann.org/apbs/) and GROMACS installations (http://www.gromacs.org). Optionally LaTeX.Nature of problem:Calculates the Molecular Mechanics (MM) data (Lennard-Jones and Coulomb terms) and the solvation energy terms (polar and nonpolar terms respectively) from an ensemble of structures derived from GROMACS molecular dynamics simulation trajectory. These calculations are performed for each single component of the simulated complex, including protein and ligand. In order to cancel out artefacts an identical grid setup for each component, including complex, protein and ligand, is required. Performs statistical analysis on the extracted data and comparison with wild-type complex in case of either computational alanine scanning or calculations on a set of simulations. Evaluates possible outliers in the frames extracted from the simulations during the binding free energy calculations.Solution method:The tool combines the freely available programs GROMACS and APBS to: 1.extract frames from a single or multiple complex molecular dynamics (MD) simulation, allowing comparison between multiple trajectories;2.split the complex frames in the single components including complex, protein and ligand;3.calculate the Lennard-Jones and Coulomb energy values (MM terms);4.calculate the polar solvation energy values using the implicit solvation Poisson–Boltzmann model (PB);5.calculate the nonpolar solvation energy value based on the solvent accessible surface area (SASA);6.combine all the calculated terms into the final binding free energy value;7.repeat the same procedure from point 1 to 6 for each simulation in case of computational alanine scanning (CAS) or simultaneous comparison of different MDs.Restrictions:Input format files compatible with GROMACS engine 4.5 and later versions. Availability of the force field or of the topology files.Running time:On a single core, Lennard-Jones, Coulomb and nonpolar solvation terms calculations require a few minutes. The time required for polar solvation terms calculations depends on the system size.