scholarly journals Practical Estimation of TCR-pMHC Binding Free-Energy Based on the Dielectric Model and the Coarse-Grained Model

10.5772/35881 ◽  
2012 ◽  
Author(s):  
Hiromichi Tsurui ◽  
Takuya Takahashi
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Dielectric Model

scholarly journals Thermodynamics of adaptive molecular resolution

2016 ◽  
Vol 374 (2080) ◽  
pp. 20160152 ◽  
Author(s):  
R. Delgado-Buscalioni
Keyword(s):  
Free Energy ◽  
Potential Energy ◽  
Local Thermodynamic Equilibrium ◽  
Thermodynamic Formalism ◽  
Energy Difference ◽  
Chem Phys ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Thermodynamic Potentials ◽  
Energy Compensation

A relatively general thermodynamic formalism for adaptive molecular resolution (AMR) is presented. The description is based on the approximation of local thermodynamic equilibrium and considers the alchemic parameter λ as the conjugate variable of the potential energy difference between the atomistic and coarse-grained model Φ = U (1) − U (0) . The thermodynamic formalism recovers the relations obtained from statistical mechanics of H-AdResS (Español et al ., J. Chem. Phys. 142 , 064115, 2015 ( doi:10.1063/1.4907006 )) and provides relations between the free energy compensation and thermodynamic potentials. Inspired by this thermodynamic analogy, several generalizations of AMR are proposed, such as the exploration of new Maxwell relations and how to treat λ and Φ as ‘real’ thermodynamic variables . This article is part of the themed issue ‘Multiscale modelling at the physics–chemistry–biology interface’.

A MODEL FOR SOLVENT MEDIATED INTERACTIONS BETWEEN MOLECULES AND SURFACES

2009 ◽  
Vol 20 (05) ◽  
pp. 747-759
Author(s):  
JUAN G. DIAZ OCHOA
Keyword(s):  
Game Theory ◽  
Free Energy ◽  
Molecular Recognition ◽  
Adsorption Energy ◽  
Energy Barrier ◽  
Energy Landscape ◽  
Explicit Representation ◽  
Coarse Grained ◽  
Free Energy Barrier ◽  
Coarse Grained Model

This work introduces a novel coarse-grained model representing the dynamics of polar molecules that adsorb on a substrate in the presence of a solvent. The motivation of the model is to avoid the explicit representation of the solvent. Instead, the solvent-mediated interaction is indirectly represented using a fluctuating energy landscape. The dynamics, on which this model is based, are similar to the dynamics in game theory. In particular, the strategy of an agent in a game is similar to the modification of the free energy barrier between the molecule and the substrate induced by other companion molecules. The aim of this method is to show how the interplay between solvents and companion molecules can imply a modification in the adsorption energy of molecules, and how this modification can buffer the adsorption of specific molecules on surfaces. The results, and their implications in the molecular recognition of surfaces, are discussed.

scholarly journals Lipids in the Piezo1 channel pore: gating mechanism, or simulation artifact?

2021 ◽  
Author(s):  
Wenjuan Jiang ◽  
Jerome Jacques Lacroix ◽  
Yun Luo
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Binding Free Energy ◽  
Simulated Data ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Computational Simulations ◽  
Gating Mechanism ◽  
Reverse Mapping ◽  
Absolute Binding Free Energy

Opening and closure of certain mechanosensitive ion channels have recently been linked with the presence of lipids in or near their pores. Although non-conducting structures of mechanosensitive Piezo channels do not show the presence of lipids in the pore, computational simulations suggest whole phospholipids enter the Piezo1 pore in the closed state. Here, to probe this phenomenon, we conduct coarse-grained (CG) and all-atom (AA) simulations of Piezo1 with different solvation algorithms and equilibrium protocols, including CG-to-AA reverse mapping from Martini CG force field to CHARMM AA force field. Our results show that the lack of initial hydration of the upper pore region, enabled by common CG but not AA solvation algorithms, allows entry of whole lipids through gaps between pore helices during subsequent equilibrium simulations. Absolute binding free energy calculations show that these lipids are thermodynamically unfavorable, indicating they are likely kinetically trapped in the pore during microsecond-long AA simulations. An alternative equilibrium protocol is proposed to avoid such simulation artifact for channels whose pores are walled with transmembrane gaps. This work underscores the notion that, as simulated systems become increasingly complex, interpretation of simulated data in physiological contexts requires extra precautions. When no experimental data is available, free energy approaches such as those implemented here appear as trustworthy validations of results observed from MD trajectories.

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Author(s):  
Christina Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculation ◽  
Large Scale Assessment ◽  
New Public ◽  
Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

Automated, Accurate, and Scalable Relative Protein-Ligand Binding Free Energy Calculations using Lambda Dynamics

2020 ◽  
Author(s):  
E. Prabhu Raman ◽  
Thomas J. Paul ◽  
Ryan L. Hayes ◽  
Charles L. Brooks III
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Computational Cost ◽  
Combinatorial Libraries ◽  
Free Energy Calculations ◽  
Lead Optimization ◽  
Efficient Estimation ◽  
Lead Compound

<p>Accurate predictions of changes to protein-ligand binding affinity in response to chemical modifications are of utility in small molecule lead optimization. Relative free energy perturbation (FEP) approaches are one of the most widely utilized for this goal, but involve significant computational cost, thus limiting their application to small sets of compounds. Lambda dynamics, also rigorously based on the principles of statistical mechanics, provides a more efficient alternative. In this paper, we describe the development of a workflow to setup, execute, and analyze Multi-Site Lambda Dynamics (MSLD) calculations run on GPUs with CHARMm implemented in BIOVIA Discovery Studio and Pipeline Pilot. The workflow establishes a framework for setting up simulation systems for exploratory screening of modifications to a lead compound, enabling the calculation of relative binding affinities of combinatorial libraries. To validate the workflow, a diverse dataset of congeneric ligands for seven proteins with experimental binding affinity data is examined. A protocol to automatically tailor fit biasing potentials iteratively to flatten the free energy landscape of any MSLD system is developed that enhances sampling and allows for efficient estimation of free energy differences. The protocol is first validated on a large number of ligand subsets that model diverse substituents, which shows accurate and reliable performance. The scalability of the workflow is also tested to screen more than a hundred ligands modeled in a single system, which also resulted in accurate predictions. With a cumulative sampling time of 150ns or less, the method results in average unsigned errors of under 1 kcal/mol in most cases for both small and large combinatorial libraries. For the multi-site systems examined, the method is estimated to be more than an order of magnitude more efficient than contemporary FEP applications. The results thus demonstrate the utility of the presented MSLD workflow to efficiently screen combinatorial libraries and explore chemical space around a lead compound, and thus are of utility in lead optimization.</p>

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

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