scholarly journals Calculating binding free energies of host–guest systems using the AMOEBA polarizable force field

2016 ◽  
Vol 18 (44) ◽  
pp. 30261-30269 ◽  
Author(s):  
David R. Bell ◽  
Rui Qi ◽  
Zhifeng Jing ◽  
Jin Yu Xiang ◽  
Christopher Mejias ◽  
...  
Keyword(s):  
Force Field ◽  
Free Energies ◽  
Polarizable Force Field ◽  
Guest Binding ◽  
Binding Free Energies

Cucurbit[7]uril host–guest binding free energies are investigated using the AMOEBA polarizable force field.

scholarly journals Accurate Calculation of Hydration Free Energies using Pair-Specific Lennard-Jones Parameters in the CHARMM Drude Polarizable Force Field

2010 ◽  
Vol 6 (4) ◽  
pp. 1181-1198 ◽  
Author(s):  
Christopher M. Baker ◽  
Pedro E. M. Lopes ◽  
Xiao Zhu ◽  
Benoît Roux ◽  
Alexander D. MacKerell
Keyword(s):  
Force Field ◽  
Free Energies ◽  
Accurate Calculation ◽  
Polarizable Force Field ◽  
Lennard Jones

scholarly journals Improving the description of interactions between Ca2+ and protein carboxylate groups, including γ-carboxyglutamic acid: revised CHARMM22* parameters

RSC Advances ◽  
2015 ◽  
Vol 5 (83) ◽  
pp. 67820-67828 ◽  
Author(s):  
Andrew T. Church ◽  
Zak E. Hughes ◽  
Tiffany R. Walsh
Keyword(s):  
Force Field ◽  
Free Energies ◽  
Carboxylate Groups ◽  
Carboxyglutamic Acid ◽  
Binding Free Energies

We show that the CHARMM22* force-field over-binds the interaction between aqueous carboxylates and Ca2+, and introduce a modification that can recover experimentally-determined binding free energies for these systems.

scholarly journals SAMPL6 Host-Guest Binding Affinities and Binding Poses from Spherical-Coordinates-Biased Simulations

2020 ◽  
Author(s):  
Zhaoxi Sun ◽  
Qiaole He ◽  
Xiao Li ◽  
Zhengdan Zhu
Keyword(s):  
Computer Simulation ◽  
Relative Position ◽  
Experimental Results ◽  
Binding Affinities ◽  
Spherical Coordinates ◽  
Challenging Problem ◽  
Free Energies ◽  
Statistical Assessment ◽  
Guest Binding ◽  
Binding Free Energies

Host-guest binding is a challenging problem in computer simulation. The prediction of binding affinities between hosts and guests is an important part of the statistical assessment of the modeling of proteins and ligands (SAMPL) challenges. In this work, the volume-based variant of well-tempered metadynamics is employed to calculate the binding affinities of the host-guest systems in the SAMPL6 challenge. By biasing the spherical coordinates describing the relative position of the host and the guest, the initial-configuration-induced bias vanishes and all possible binding poses are explored. The agreement between the predictions and the experimental results and the observation of new binding poses indicate that the volume-based technique serves as a nice candidate for the calculation of binding free energies and the search of the binding poses.

scholarly journals Binding thermodynamics of host-guest systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

2019 ◽  
Author(s):  
David Slochower ◽  
Niel Henriksen ◽  
Lee-Ping Wang ◽  
John Chodera ◽  
David Mobley ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Force Field ◽  
Small Molecule ◽  
Force Fields ◽  
Free Energy Calculations ◽  
Model Systems ◽  
Conformational Space ◽  
Free Energies ◽  
Binding Thermodynamics ◽  
Binding Free Energies

<div><div><div><p>Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small- molecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a drug-like guest molecules have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose systems that avoid ambiguities in protonation states. These features, combined with their ease of experimental characterization, make host-guest systems ideal model systems to test and ultimately optimize force fields in the context of binding thermodynamics calculations.</p><p><br></p><p>The Open Force Field Initiative aims to create a modern, open software infrastructure for automatically generating and assessing force fields using data sets. The first force field to arise out of this effort, named SMIRNOFF99Frosst, has approximately one tenth the number of parameters, in version 1.0.5, compared to typical general small molecule force fields, such as GAFF. Here, we evaluate the accuracy of this initial force field, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs for which experimental thermodynamic data are available, and compare with matched calculations using two versions of GAFF. For all three force fields, we used TIP3P water and AM1-BCC charges. The calculations are performed using the attach-pull-release (APR) method as implemented in the open source package, pAPRika. For binding free energies, the root mean square error of the SMIRNOFF99Frosst calculations relative to experiment is 0.9 [0.7, 1.1] kcal/mol, while the corresponding results for GAFF 1.7 and GAFF 2.1 are 0.9 [0.7, 1.1] kcal/mol and 1.7 [1.5, 1.9] kcal/mol, respectively, with 95% confidence ranges in brackets. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.</p></div></div></div>

scholarly journals SAMPL6 Host-Guest Binding Affinities and Binding Poses from Spherical-Coordinates-Biased Simulations

2020 ◽  
Author(s):  
Zhaoxi Sun ◽  
Qiaole He ◽  
Xiao Li ◽  
Zhengdan Zhu
Keyword(s):  
Computer Simulation ◽  
Relative Position ◽  
Experimental Results ◽  
Binding Affinities ◽  
Spherical Coordinates ◽  
Challenging Problem ◽  
Free Energies ◽  
Statistical Assessment ◽  
Guest Binding ◽  
Binding Free Energies

Host-guest binding is a challenging problem in computer simulation. The prediction of binding affinities between hosts and guests is an important part of the statistical assessment of the modeling of proteins and ligands (SAMPL) challenges. In this work, the volume-based variant of well-tempered metadynamics is employed to calculate the binding affinities of the host-guest systems in the SAMPL6 challenge. By biasing the spherical coordinates describing the relative position of the host and the guest, the initial-configuration-induced bias vanishes and all possible binding poses are explored. The agreement between the predictions and the experimental results and the observation of new binding poses indicate that the volume-based technique serves as a nice candidate for the calculation of binding free energies and the search of the binding poses.

Bind3P: A Water Model to Improve the Accuracy of Binding Calculations

2018 ◽  
Author(s):  
Jian Yin ◽  
Niel M. Henriksen ◽  
Hari S. Muddana ◽  
Michael K. Gilson
Keyword(s):  
Pure Water ◽  
Bulk Water ◽  
Water Model ◽  
Pure Liquid ◽  
Free Energies ◽  
Water Properties ◽  
Binding Data ◽  
Guest Binding ◽  
The Mean ◽  
Binding Free Energies

We report a water model, Bind3P (Version 0.1), which was obtained by using sensitivity analysis to readjust the Lennard-Jones parameters of the TIP3P model against experimental binding free energies for six host-guest systems, along with pure liquid properties. Tests of Bind3P against >100 experimental binding free energies and enthalpies for host-guest systems distinct from the training set show a consistent drop in the mean signed error, relative to matched calculations with TIP3P. Importantly, Bind3P preserves the accuracy of bulk water properties, such as density and heat of vaporization. The same approach can be applied to more sophisticated water models that can better represent pure water properties. These results lend further support to concept of integrating host-guest binding data into force field parameterization.

scholarly journals Computation of protein–ligand binding free energies using quantum mechanical bespoke force fields

MedChemComm ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 1116-1120 ◽  
Author(s):  
Daniel J. Cole ◽  
Israel Cabeza de Vaca ◽  
William L. Jorgensen
Keyword(s):  
Ligand Binding ◽  
Force Field ◽  
Molecular Mechanics ◽  
Force Fields ◽  
Quantum Mechanical ◽  
T4 Lysozyme ◽  
Free Energies ◽  
Binding Free Energies

A quantum mechanical bespoke molecular mechanics force field is derived for the L99A mutant of T4 lysozyme and used to compute absolute binding free energies of six benzene analogs to the protein.

scholarly journals Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

2016 ◽  
Vol 37 (32) ◽  
pp. 2749-2758 ◽  
Author(s):  
Noor Asidah Mohamed ◽  
Richard T. Bradshaw ◽  
Jonathan W. Essex
Keyword(s):  
Force Field ◽  
Small Molecules ◽  
Free Energies ◽  
Polarizable Force Field ◽  
Solvation Free Energies
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