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

2019 ◽  
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.

SAMPL7 TrimerTrip Host-Guest Binding Poses and Binding Affinities from Spherical-Coordinates-Biased Simulations

2020 ◽  
Author(s):  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Energy Estimates ◽  
Binding Affinities ◽  
Spherical Coordinates ◽  
Collective Variables ◽  
Guest Binding ◽  
Starting Point ◽  
Sampl Challenge

Host-guest binding remains a major challenge in modern computational modelling. The newest 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge contains a new series of host-guest systems. The TrimerTrip host binds to 16 structurally diverse guests. Previously, we have successfully employed the spherical coordinates as the collective variables coupled with the enhanced sampling technique metadynamics to enhance the sampling of the binding/unbinding event, search for possible binding poses and predict the binding affinities in all three host-guest binding cases of the 6<sup>th</sup> SAMPL challenge. In this work, we employed the same protocol to investigate the TrimerTrip host in the SAMPL7 challenge. As no binding pose is provided by the SAMPL7 host, our simulations initiate from randomly selected configurations and are proceeded long enough to obtain converged free energy estimates and search for possible binding poses. The predicted binding affinities are in good agreement with the experimental reference, and the obtained binding poses serve as a nice starting point for end-point or alchemical free energy calculations.

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.

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.

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

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

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.

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