scholarly journals Massive-Scale Binding Free Energy Simulations of HIV Integrase Complexes Using Asynchronous Replica Exchange Framework Implemented on the IBM WCG Distributed Network

2019 ◽  
Vol 59 (4) ◽  
pp. 1382-1397 ◽  
Author(s):  
Junchao Xia ◽  
William Flynn ◽  
Emilio Gallicchio ◽  
Keith Uplinger ◽  
Jonathan D. Armstrong ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Replica Exchange ◽  
Distributed Network ◽  
Hiv Integrase ◽  
Massive Scale ◽  
Energy Simulations

scholarly journals New Tools for Conformational and Binding Free Energy Simulations

2019 ◽  
Vol 116 (3) ◽  
pp. 142a
Author(s):  
Giacomo Fiorin ◽  
Grace Brannigan ◽  
Jérôme Hénin
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Energy Simulations

scholarly journals Rapid, accurate, precise and reproducible ligand–protein binding free energy prediction

2020 ◽  
Vol 10 (6) ◽  
pp. 20200007 ◽  
Author(s):  
Shunzhou Wan ◽  
Agastya P. Bhati ◽  
Stefan J. Zasada ◽  
Peter V. Coveney
Keyword(s):  
Free Energy ◽  
Initial Conditions ◽  
Binding Free Energy ◽  
Computational Cost ◽  
Free Energy Calculations ◽  
Enhanced Sampling ◽  
Energy Prediction ◽  
Massive Scale ◽  
Chaotic Nature ◽  
High Level

A central quantity of interest in molecular biology and medicine is the free energy of binding of a molecule to a target biomacromolecule. Until recently, the accurate prediction of binding affinity had been widely regarded as out of reach of theoretical methods owing to the lack of reproducibility of the available methods, not to mention their complexity, computational cost and time-consuming procedures. The lack of reproducibility stems primarily from the chaotic nature of classical molecular dynamics (MD) and the associated extreme sensitivity of trajectories to their initial conditions. Here, we review computational approaches for both relative and absolute binding free energy calculations, and illustrate their application to a diverse set of ligands bound to a range of proteins with immediate relevance in a number of medical domains. We focus on ensemble-based methods which are essential in order to compute statistically robust results, including two we have recently developed, namely thermodynamic integration with enhanced sampling and enhanced sampling of MD with an approximation of continuum solvent. Together, these form a set of rapid, accurate, precise and reproducible free energy methods. They can be used in real-world problems such as hit-to-lead and lead optimization stages in drug discovery, and in personalized medicine. These applications show that individual binding affinities equipped with uncertainty quantification may be computed in a few hours on a massive scale given access to suitable high-end computing resources and workflow automation. A high level of accuracy can be achieved using these approaches.

scholarly journals CHARMM-GUI Free Energy Calculator for Absolute and Relative Ligand Solvation and Binding Free Energy Simulations

2020 ◽  
Vol 16 (11) ◽  
pp. 7207-7218 ◽  
Author(s):  
Seonghoon Kim ◽  
Hiraku Oshima ◽  
Han Zhang ◽  
Nathan R. Kern ◽  
Suyong Re ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Energy Simulations

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 Capturing the Flexibility of a Protein-Ligand Complex: Binding Free Energies from Different Enhanced Sampling Techniques

2020 ◽  
Author(s):  
Sebastian Wingbermühle ◽  
Lars V. Schäfer
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Replica Exchange ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Ligand Complex ◽  
Mhc I ◽  
Partial Dissociation

Enhanced sampling techniques are a promising approach to obtain reliable binding free energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*35:01 to systematically investigate the performance of Umbrella Sampling (US), Replica Exchange with Solute Tempering 2 (REST2), Bias Exchange Umbrella Sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered Metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can handle best the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free energy minimum in the pMHC I under study. These findings might be relevant also for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.<br>

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