scholarly journals Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages

2018 ◽  
Vol 14 (11) ◽  
pp. 5567-5582 ◽  
Author(s):  
Hannes H. Loeffler ◽  
Stefano Bosisio ◽  
Guilherme Duarte Ramos Matos ◽  
Donghyuk Suh ◽  
Benoit Roux ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Simulation ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Software Packages

scholarly journals Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software

2018 ◽  
Author(s):  
Hannes H. Loeffler ◽  
Stefano Bosisio ◽  
Guilherme Duarte Ramos Matos ◽  
Donghyuk Suh ◽  
Benoît Roux ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Simulation ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Small Organic Molecules ◽  
Energy Calculations ◽  
Alchemical Free Energy ◽  
Attention To Detail ◽  
Alchemical Free Energy Calculations

<div> <div> <div> <p>Alchemical free energy calculations are an increasingly important modern simulation technique. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS and SOMD include support for the method. Implementation details vary among those codes but users expect reliability and reproducibility, i.e. for a given molec- ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy (RAFE) simulation is increasingly used to support molecule discovery projects, yet the reproducibility of the methodology has been less well tested than its absolute counter- part. Here we present RAFE calculations of hydration free energies for a set of small organic molecules and demonstrate that free energies can be reproduced to within about 0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires considerable attention to detail and package–specific simulation protocols, and no uni- versally applicable protocol emerges. The benchmarks and protocols reported here should be useful for the community to validate new and future versions of software for free energy calculations.</p></div></div></div>

scholarly journals Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software

2018 ◽  
Author(s):  
Hannes H. Loeffler ◽  
Stefano Bosisio ◽  
Guilherme Duarte Ramos Matos ◽  
Donghyuk Suh ◽  
Benoît Roux ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Simulation ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Small Organic Molecules ◽  
Energy Calculations ◽  
Alchemical Free Energy ◽  
Attention To Detail ◽  
Alchemical Free Energy Calculations

<div> <div> <div> <p>Alchemical free energy calculations are an increasingly important modern simulation technique. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS and SOMD include support for the method. Implementation details vary among those codes but users expect reliability and reproducibility, i.e. for a given molec- ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy (RAFE) simulation is increasingly used to support molecule discovery projects, yet the reproducibility of the methodology has been less well tested than its absolute counter- part. Here we present RAFE calculations of hydration free energies for a set of small organic molecules and demonstrate that free energies can be reproduced to within about 0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires considerable attention to detail and package–specific simulation protocols, and no uni- versally applicable protocol emerges. The benchmarks and protocols reported here should be useful for the community to validate new and future versions of software for free energy calculations.</p></div></div></div>

scholarly journals Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations

2020 ◽  
Author(s):  
Ido Ben-Shalom ◽  
Zhixiong Lin ◽  
Brian Radak ◽  
Charles Lin ◽  
Woody Sherman ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Site ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Computer Hardware ◽  
Water Molecules ◽  
Energy Calculations ◽  
Binding Free Energy Calculations

Rigorous binding free energy methods in drug discovery are growing in popularity due to a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all the binding site is inaccessible to bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting Ligand 1 to Ligand 2 within the binding site. Thus, if Ligand 1 is smaller and/or more polar than Ligand 2, the perturbation may allow additional water molecules to occupy a region of the binding site. However, this change in hydration may not be captured by standard MD simulations and may therefore lead to errors in the computed free energy. We recently developed a hybrid Monte Carlo/MD (MC/MD) method, which speeds the equilibration of water between bulk solvent and buried cavities, while sampling from the intended distribution of states. Here, we report on the use of this approach in the context of alchemical binding free energy calculations. We find that using MC/MD markedly improves the accuracy of the calculations and also reduces hysteresis between the forward and reverse perturbations, relative to matched calculations using only MD with or without the crystallographic water molecules. The present method is available for use in the AMBER simulation software.<br>

scholarly journals Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations

2020 ◽  
Author(s):  
Ido Ben-Shalom ◽  
Zhixiong Lin ◽  
Brian Radak ◽  
Charles Lin ◽  
Woody Sherman ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Site ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Computer Hardware ◽  
Water Molecules ◽  
Energy Calculations ◽  
Binding Free Energy Calculations

Rigorous binding free energy methods in drug discovery are growing in popularity due to a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all the binding site is inaccessible to bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting Ligand 1 to Ligand 2 within the binding site. Thus, if Ligand 1 is smaller and/or more polar than Ligand 2, the perturbation may allow additional water molecules to occupy a region of the binding site. However, this change in hydration may not be captured by standard MD simulations and may therefore lead to errors in the computed free energy. We recently developed a hybrid Monte Carlo/MD (MC/MD) method, which speeds the equilibration of water between bulk solvent and buried cavities, while sampling from the intended distribution of states. Here, we report on the use of this approach in the context of alchemical binding free energy calculations. We find that using MC/MD markedly improves the accuracy of the calculations and also reduces hysteresis between the forward and reverse perturbations, relative to matched calculations using only MD with or without the crystallographic water molecules. The present method is available for use in the AMBER simulation software.<br>

Free-energy calculations for fluid and solid phases by molecular simulation

2002 ◽  
Vol 194-197 ◽  
pp. 219-226 ◽  
Author(s):  
Nandou Lu ◽  
C. Daniel Barnes ◽  
David A. Kofke
Keyword(s):  
Free Energy ◽  
Molecular Simulation ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Solid Phases

Free-energy calculations using classical molecular simulation: application to the determination of the melting point and chemical potential of a flexible RDX model

2016 ◽  
Vol 18 (11) ◽  
pp. 7841-7850 ◽  
Author(s):  
Michael S. Sellers ◽  
Martin Lísal ◽  
John K. Brennan
Keyword(s):  
Free Energy ◽  
Melting Point ◽  
Molecular Simulation ◽  
Chemical Potential ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Liquid Phases

Several methods are used in sequence to determine the chemical potential of atomistic RDX in the solid and liquid phases, and its corresponding melting point. Results yield the thermodynamic melting point of 488.75 K at 1.0 atm.

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