scholarly journals Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Drug Candidates ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

scholarly journals Automated docking refinement and virtual compound screening with absolute binding free energy calculations

2020 ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Absolute Binding Free Energy ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to fully automate the calculation of binding free energies for a protein with a series of ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost allows this procedure to be applied in a relatively high-throughput mode, and thus enables new applications in early-stage drug discovery.

scholarly journals Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

2021 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresdern ◽  
Matteo Aldeghi ◽  
Hannah Magdalena Baumann ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Drug Design ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains...

scholarly journals Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

2021 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresadern ◽  
Matteo Aldeghi ◽  
Hannah Magdalena Baumann ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies ◽  
Apo State

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based absolute binding free energy estimates for 128 pharmaceutically relevant targets. We use a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Not only do the calculations deliver accurate protein-ligand binding affinity estimates, but they also provide detailed physical insight into the structural determinants of binding. We identify subtle rotamer rearrangements between apo and holo states of a protein that are crucial for binding. When compared to relative binding free energy calculations, obtaining absolute binding free energies is considerably more challenging in large part due to the need to explicitly account for the protein in its apo state. In this work we present several approaches to obtain apo state ensembles for accurate absolute ΔG calculations, thus outlining protocols for prospective application of the methods for drug discovery.

scholarly journals Predicting binding free energies: Frontiers and benchmarks

2016 ◽  
Author(s):  
David L. Mobley ◽  
Michael K. Gilson
Keyword(s):  
Molecular Design ◽  
Early Stage ◽  
Binding Free Energy ◽  
Research Community ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Free Energies ◽  
Biomolecular Complexes ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions between its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early stage drug discovery. However, many challenges remain to make them a robust and reliable tool. Here, we briefly explain how the calculations work, highlight key challenges, and argue for the development of accepted benchmark test systems that will help the research community generate and evaluate progress.Manuscript version 1.1.1 pre-release See https://github.com/mobleylab/benchmarksets for all versions.

scholarly journals A replica exchange umbrella sampling (REUS) approach to predict host–guest binding free energies in SAMPL8 challenge

2021 ◽  
Author(s):  
Mahdi Ghorbani ◽  
Phillip S. Hudson ◽  
Michael R. Jones ◽  
Félix Aviat ◽  
Rubén Meana-Pañeda ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Free Energy Calculations ◽  
Replica Exchange ◽  
Free Energies ◽  
Guest Binding ◽  
Binding Free Energy Calculations ◽  
Force Field Parameters ◽  
Binding Free Energies

AbstractIn this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host–guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 $${\text{kcal}}/{\text{mol}}$$ kcal / mol from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of $$2.65$$ 2.65 and $$1.72 {\text{kcal}}/{\text{mol}}$$ 1.72 kcal / mol , respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.

scholarly journals An Approach to Alchemical Binding Free-Energy Calculations Using Coupled Topologies

2018 ◽  
Author(s):  
David Huggins
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Bound State ◽  
Free Energy Calculations ◽  
Test Case ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Good Agreement ◽  
Absolute Binding Free Energy

<p>We present an approach to performing alchemical binding free energies which we term coupled topologies. Simultaneously coupling a molecule in the bound state while decoupling it in the unbound state allows us to calculate free energy changes where the system changes charge, without the need to correct for simulation artifacts. This solves a longstanding problem in computing free energy changes. The approach is applied to separated topology relative binding free energy calculations, but is appropriate for single topology calculations and dual topology calculations as well as absolute binding free energy calculations. We apply the method to small-molecule inhibitors of AmpC β-lactamase and show the coupled topologies approach yields results that are in excellent agreement with experiment and good agreement with a state-of-the-art separated topology approach. The promising results on this test case suggest that the coupled topologies approach will be a useful addition to the available arsenal of free-energy methods.</p>

scholarly journals An Approach to Alchemical Binding Free-Energy Calculations Using Coupled Topologies

2018 ◽  
Author(s):  
David Huggins
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Bound State ◽  
Free Energy Calculations ◽  
Test Case ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Good Agreement ◽  
Absolute Binding Free Energy

<p>We present an approach to performing alchemical binding free energies which we term coupled topologies. Simultaneously coupling a molecule in the bound state while decoupling it in the unbound state allows us to calculate free energy changes where the system changes charge, without the need to correct for simulation artifacts. This solves a longstanding problem in computing free energy changes. The approach is applied to separated topology relative binding free energy calculations, but is appropriate for single topology calculations and dual topology calculations as well as absolute binding free energy calculations. We apply the method to small-molecule inhibitors of AmpC β-lactamase and show the coupled topologies approach yields results that are in excellent agreement with experiment and good agreement with a state-of-the-art separated topology approach. The promising results on this test case suggest that the coupled topologies approach will be a useful addition to the available arsenal of free-energy methods.</p>

scholarly journals A Benchmark of Electrostatic Methods Performance in Relative Binding Free Energy Calculations

2020 ◽  
Author(s):  
Yunhui Ge ◽  
David F. Hahn ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Reaction Field ◽  
Know How ◽  
Particle Mesh Ewald ◽  
Relative Binding ◽  
Binding Free Energy Calculations

<div><div><div><p>Relative free energy calculations are fast becoming a critical part of early stage pharmaceu- tical design, making it important to know how to obtain the best performance with these calculations in applications which could span hundreds of calculations and molecules. In this work, we compared two different treatments of long-range electrostatics, Particle Mesh Ewald (PME) and Reaction Field (RF), in relative binding free energy calculations using a non-equilibrium switching protocol. We found simulations using RF achieve comparable re- sults as those using PME but gain more efficiency when using CPU and similar performance using GPU. The results from this work encourage more use of RF in molecular simulations.</p></div></div></div>

scholarly journals A Benchmark of Electrostatic Methods Performance in Relative Binding Free Energy Calculations

2020 ◽  
Author(s):  
Yunhui Ge ◽  
David F. Hahn ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Reaction Field ◽  
Know How ◽  
Particle Mesh Ewald ◽  
Relative Binding ◽  
Binding Free Energy Calculations

<div><div><div><p>Relative free energy calculations are fast becoming a critical part of early stage pharmaceu- tical design, making it important to know how to obtain the best performance with these calculations in applications which could span hundreds of calculations and molecules. In this work, we compared two different treatments of long-range electrostatics, Particle Mesh Ewald (PME) and Reaction Field (RF), in relative binding free energy calculations using a non-equilibrium switching protocol. We found simulations using RF achieve comparable re- sults as those using PME but gain more efficiency when using CPU and similar performance using GPU. The results from this work encourage more use of RF in molecular simulations.</p></div></div></div>

scholarly journals A Benchmark of Electrostatic Methods Performance in Relative Binding Free Energy Calculations

2021 ◽  
Author(s):  
Yunhui Ge ◽  
David F. Hahn ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Reaction Field ◽  
Know How ◽  
Particle Mesh Ewald ◽  
Relative Binding ◽  
Binding Free Energy Calculations

<div><div><div><p>Relative free energy calculations are fast becoming a critical part of early stage pharmaceu- tical design, making it important to know how to obtain the best performance with these calculations in applications which could span hundreds of calculations and molecules. In this work, we compared two different treatments of long-range electrostatics, Particle Mesh Ewald (PME) and Reaction Field (RF), in relative binding free energy calculations using a non-equilibrium switching protocol. We found simulations using RF achieve comparable re- sults as those using PME but gain more efficiency when using CPU and similar performance using GPU. The results from this work encourage more use of RF in molecular simulations.</p></div></div></div>

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