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.

scholarly journals SAMPL7 Challenge Overview: Assessing the Reliability of Polarizable and Non-Polarizable Methods for Host-Guest Binding Free Energy Calculations

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

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 a 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 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.

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 On the Role of Dewetting Transitions in Host–Guest Binding Free Energy Calculations

2012 ◽  
Vol 9 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Kathleen E. Rogers ◽  
Juan Manuel Ortiz-Sánchez ◽  
Riccardo Baron ◽  
Mikolai Fajer ◽  
César Augusto F. de Oliveira ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Guest Binding ◽  
Binding Free Energy Calculations

scholarly journals Challenges Encountered Applying Equilibrium and Non-Equilibrium Binding Free Energy Calculations

2020 ◽  
Author(s):  
Hannah Baumann ◽  
Vytautas Gapsys ◽  
Bert L. de Groot ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Future Research ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Sampling Problems ◽  
Alchemical Free Energy ◽  
Non Equilibrium

<div>Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. </div><div>However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique.</div><div>In this paper we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and non-equilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are likely to show up in other protein-ligand systems as well and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the non-equilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area. </div>

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 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 Drug Repurposing of Allophenylnorstatine Containing HIV-Protease Inhibitors Against SARS-CoV-2 Mpro: Insights from Molecular Dynamics Simulations and Binding Free Energy Estimations

2020 ◽  
Author(s):  
Jiban Jyoti Dash ◽  
Priyanka Purohit ◽  
Jules Tshishimbi Muya ◽  
Biswa Ranjan Meher
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Protease Inhibitors ◽  
Active Site ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Binding Affinities ◽  
Solvation Energies

Coronavirus-2 Main protease (SARS-CoV-2 M<sup>pro</sup>), one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and a crucial target for drug discovery, has been battered with numerous types of drugs/inhibitors. Regrettably, till date there is no any potential drugs or effective inhibitors available to combat its action. Based on the reports of HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M<sup>pro</sup>, we have chosen few clinically trialed experimental HIV-protease inhibitors (JE-2147, KNI-227 and KNI-272) and a variant JE2-CH3, to examine their binding affinities with SARS-CoV-2 M<sup>pro</sup> and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the rational elucidation of the binding mechanism of these four inhibitors to SARS-CoV-2 M<sup>pro</sup> by merging molecular docking, Molecular Dynamics (MD) simulation, and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (-14.95 kcal/mol) compared to JE2-CH3 (--11.19 kcal/mol), KNI-227 (-13.93 kcal/mol) and KNI-272 (-12.84 kcal/mol) against SARS-CoV-2 M<sup>pro</sup>. The increase in binding affinity for JE-2147 comparative to other three inhibitors arises due to an increased favorable van der Waals interactions and decreased solvation energies between the inhibitor and viral protease. Residue decomposition analysis and hydrogen bonding pattern confirms binding affinities of the inhibitors crucial for the interactions. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Pro168, Gln189 etc.) from the active site or near the active site regions with more than 1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 M<sup>pro</sup> drugs. <br>

scholarly journals Challenges Encountered Applying Equilibrium and Non-Equilibrium Binding Free Energy Calculations

2021 ◽  
Author(s):  
Hannah Baumann ◽  
Vytautas Gapsys ◽  
Bert L. de Groot ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Future Research ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Sampling Problems ◽  
Alchemical Free Energy ◽  
Non Equilibrium

<div>Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. </div><div>However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique.</div><div>In this paper we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and non-equilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are likely to show up in other protein-ligand systems as well and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the non-equilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area. </div>

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