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

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 also yields some improvement in the hydration free energies of small organic molecules, and preserves the accuracy of bulk water properties, such as density and the 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.

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Bind3P: Optimization of a Water Model with Host-Guest Binding Data

10.26434/chemrxiv.5848113 ◽

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 also yields some improvement in the hydration free energies of small organic molecules, and preserves the accuracy of bulk water properties, such as density and the 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.

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Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

Journal of Chemical Theory and Computation ◽

10.1021/acs.jctc.8b00318 ◽

2018 ◽

Vol 14 (7) ◽

pp. 3621-3632 ◽

Cited By ~ 8

Author(s):

Jian Yin ◽

Niel M. Henriksen ◽

Hari S. Muddana ◽

Michael K. Gilson

Keyword(s):

Water Model ◽

Model Based ◽

Binding Data ◽

Guest Binding

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

10.26434/chemrxiv.11472639 ◽

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.

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

10.26434/chemrxiv.11472639.v2 ◽

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.

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On the fly estimation of host–guest binding free energies using the movable type method: participation in the SAMPL5 blind challenge

Journal of Computer-Aided Molecular Design ◽

10.1007/s10822-016-9980-6 ◽

2016 ◽

Vol 31 (1) ◽

pp. 47-60 ◽

Cited By ~ 8

Author(s):

Nupur Bansal ◽

Zheng Zheng ◽

David S. Cerutti ◽

Kenneth M. Merz

Keyword(s):

Free Energies ◽

Type Method ◽

Blind Challenge ◽

Guest Binding ◽

Binding Free Energies

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Computation of host–guest binding free energies with a new quantum mechanics based mining minima algorithm

The Journal of Chemical Physics ◽

10.1063/5.0040759 ◽

2021 ◽

Vol 154 (10) ◽

pp. 104122

Author(s):

Peng Xu ◽

Tosaporn Sattasathuchana ◽

Emilie Guidez ◽

Simon P. Webb ◽

Kilinoelani Montgomery ◽

...

Keyword(s):

Quantum Mechanics ◽

Free Energies ◽

Guest Binding ◽

Binding Free Energies ◽

Mining Minima

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

Journal of Computer-Aided Molecular Design ◽

10.1007/s10822-021-00385-7 ◽

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.

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Computational Analysis of Residue-Specific Binding Free Energies of Androgen Receptor to Ligands

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.646524 ◽

2021 ◽

Vol 8 ◽

Author(s):

Guangfeng Shao ◽

Jingxiao Bao ◽

Xiaolin Pan ◽

Xiao He ◽

Yifei Qi ◽

...

Keyword(s):

Androgen Receptor ◽

Specific Binding ◽

Entropy Method ◽

Van Der Waals Interactions ◽

Complex Structures ◽

Free Energies ◽

Binding Data ◽

Dynamics Simulations ◽

Important Therapeutic Target ◽

Binding Free Energies

Androgen receptor (AR) is an important therapeutic target for the treatment of diseases such as prostate cancer, hypogonadism, muscle wasting, etc. In this study, the complex structures of the AR ligand-binding domain (LBD) with fifteen ligands were analyzed by molecular dynamics simulations combined with the alanine-scanning-interaction-entropy method (ASIE). The quantitative free energy contributions of the pocket residues were obtained and hotspot residues are quantitatively identified. Our calculation shows that that these hotspot residues are predominantly hydrophobic and their interactions with binding ligands are mainly van der Waals interactions. The total binding free energies obtained by summing over binding contributions by individual residues are in good correlation with the experimental binding data. The current quantitative analysis of binding mechanism of AR to ligands provides important insight on the design of future inhibitors.

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