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 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 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 SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

2020 ◽  
Author(s):  
Zhe Huai ◽  
Huaiyu Yang ◽  
Xiao Li ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Enhanced Sampling ◽  
New Host ◽  
Energy Calculations ◽  
Configurational Space ◽  
End Point ◽  
Guest Binding

<p>The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip is synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host are characterized. The challenge provides only structures of the host and the guests, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates show significant deviations. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is already very long and the intermediate spacing is very dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. </p>

scholarly journals SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

2020 ◽  
Author(s):  
Zhe Huai ◽  
Huaiyu Yang ◽  
Xiao Li ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Enhanced Sampling ◽  
New Host ◽  
Energy Calculations ◽  
Configurational Space ◽  
End Point ◽  
Guest Binding

<p></p><p> The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent. </p><p></p>

scholarly journals SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

2020 ◽  
Author(s):  
Zhe Huai ◽  
Huaiyu Yang ◽  
Xiao Li ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Enhanced Sampling ◽  
New Host ◽  
Energy Calculations ◽  
Configurational Space ◽  
End Point ◽  
Guest Binding

<p></p><p> The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent. </p><p></p>

scholarly journals SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

2020 ◽  
Author(s):  
Martin Amezcua ◽  
Léa El Khoury ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Conformational Sampling ◽  
Binding Affinities ◽  
Polarizable Force Field ◽  
Polarizable Force Fields ◽  
Guest Binding ◽  
Multiple Conformations ◽  
Sampling Problems

The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories -- a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that alchemical free energy methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.

scholarly journals SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

2020 ◽  
Author(s):  
Martin Amezcua ◽  
Léa El Khoury ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Conformational Sampling ◽  
Binding Affinities ◽  
Polarizable Force Field ◽  
Polarizable Force Fields ◽  
Guest Binding ◽  
Multiple Conformations ◽  
Sampling Problems

The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories -- a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that alchemical free energy methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.

Automated Assessment of Binding Affinity via Alchemical Free Energy Calculations

2020 ◽  
Author(s):  
Maximilian Kuhn ◽  
Stuart Firth-Clark ◽  
Paolo Tosco ◽  
Antonia S. J. S. Mey ◽  
Mark Mackey ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Structures ◽  
Free Energy Calculations ◽  
Distinct Advantage ◽  
Binding Affinities ◽  
Structure Based Drug Design ◽  
Energy Calculations ◽  
Kendall’S Τ ◽  
Experimental Values ◽  
Better Than

Free energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace and OpenMM and uses the AMBER14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall’s τ was 0.53 ± 0.05 which is broadly comparable to or better than previously reported results using other methods. <br>

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