Protein–Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems

Kohut, Gergely; Liwo, Adam; Bősze, Szilvia; Beke‐Somfai, Tamás; Samsonov, Sergey A.

doi:10.1021/acs.jpcb.8b03658

Cited by 16 publications

(15 citation statements)

References 45 publications

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“…In the RP method, TP is used to estimate the free energy difference between state 2 and state 2′. As exponential averaging may face convergence problems, the Wu–Kofke Pi (П) value is used to check the convergence of TP corrections . As shown in the Supporting Information Table S1, all П values are larger than 0.5, which means the TP estimations are free of bias.…”

Section: Resultsmentioning

confidence: 99%

Solvation Free Energy Calculations: The Combination between the Implicitly Polarized Fixed‐charge Model and the Reference Potential Strategy

Jia

2019

J Comput Chem

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The IPolQ‐Mod charges, which are the average of two charge sets fitted in vacuum state and condensed phase, take account of polarization effect implicitly in the solvation free energy calculation. However, the performance of the IPolQ‐Mod charges sensitively depends on the QM levels used to generate the electrostatic potential from which the charges are fitted. In addition, the forces on atoms are not accurate theoretically in the molecular dynamics (MD) simulation as the solvent only feels the electrostatic potential of a half‐polarized density of the solute according to the derivation of the IPolQ‐Mod charges. To study these issues in detail, the IPolQ‐Mod charges are combined with the reference potential (RP) strategy to predict the solvation free energies in the present study. It is found that the thermodynamic perturbation (TP) corrections utilizing total energy difference and interaction energy difference are almost the same and free of bias. The solvation free energies estimated by the RP method match very well with those obtained by applying IPolQ‐Mod charges into MD simulation directly. By means of the RP strategy, the performances of the IPolQ‐Mod charges with the change of the strength of the exact HF exchange in several DFT functionals are determined effectively. Although the “optimal” strengths are found in B3LYP and LC‐ωPBE, the improvements over the default strength are not too much. In addition to the IPolQ‐Mod charges, other charge models like bond charge correction (BCC) charges could also be combined with the RP strategy to study the thermodynamic properties like solvation free energy. © 2019 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Solvation Free Energy Calculations: The Combination between the Implicitly Polarized Fixed‐charge Model and the Reference Potential Strategy

Jia

2019

J Comput Chem

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“…Interestingly, quite substantial differences in the resulting free energies of binding using NM and IE were encountered in several studies. 95,97,98 In a recent study of Sun et al, 97 entropy effects on the performance of endpoint methods of over 1,500 protein-ligand systems were assessed. The best correlation to the experimental binding affinities was gained with IE, whereas the absolute binding free energy values had the highest correspondence to experimental values using NM calculations.…”

Section: Force Field and Knowledge-based Scoring Methods For Ranking And To Predict Binding Affinitiesmentioning

confidence: 99%

“…The best correlation to the experimental binding affinities was gained with IE, whereas the absolute binding free energy values had the highest correspondence to experimental values using NM calculations. Recently, however, Kohut et al 98 proposed that the reproducibility of IE is less robust than that of NM or QH, especially for flexible systems. The calculated entropy value is mainly determined by the highest spikes of interaction energy and it is argued that the calculated entropies are difficult to converge as the simulations are prolonged.…”

Section: Force Field and Knowledge-based Scoring Methods For Ranking And To Predict Binding Affinitiesmentioning

confidence: 99%

“…IE has been successfully applied in studies in combination with MM‐PBSA and MM‐GBSA calculations of protein–protein or protein–ligand binding affinities. Interestingly, quite substantial differences in the resulting free energies of binding using NM and IE were encountered in several studies . In a recent study of Sun et al, entropy effects on the performance of endpoint methods of over 1,500 protein–ligand systems were assessed.…”

Section: Mm‐poisson–boltzmann/surface Area and Mm‐generalized Born/sumentioning

confidence: 99%

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Computational prediction of protein–protein binding affinities

Siebenmorgen

Zacharias

2019

WIREs Comput Mol Sci

130

128

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Protein–protein interactions form central elements of almost all cellular processes. Knowledge of the structure of protein–protein complexes but also of the binding affinity is of major importance to understand the biological function of protein–protein interactions. Even weak transient protein–protein interactions can be of functional relevance for the cell during signal transduction or regulation of metabolism. The structure of a growing number of protein–protein complexes has been solved in recent years. Combined with docking approaches or template‐based methods, it is possible to generate structural models of many putative protein–protein complexes or to design new protein–protein interactions. In order to evaluate the functional relevance of putative or predicted protein–protein complexes, realistic binding affinity prediction is of increasing importance. Several computational tools ranging from simple force‐field or knowledge‐based scoring of single protein–protein complexes to ensemble‐based approaches and rigorous binding free energy simulations are available to predict relative and absolute binding affinities of complexes. With a focus on molecular mechanics force‐field approaches the present review aims at presenting an overview on available methods and discussing advantages, approximations, and limitations of the various methods. This article is categorized under: Molecular and Statistical Mechanics > Molecular Interactions Molecular and Statistical Mechanics > Free Energy Methods Software > Molecular Modeling

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“…Binding energy consists of an enthalpic (sometimes referred to as a favourable) component and an entropic (sometimes referred to as an unfavourable) component. While many computational approaches are capable of accurately predicting changes in the enthalpic component, entropic contributions are more challenging to predict [31,32] and are often outright ignored [33,34]. The predicted loss in receptor binding affinity upon mutation of residues 3 and 12 is likely to be largely associated with a reduction in the enthalpic contribution to the binding energy.…”

Section: Discussionmentioning

confidence: 99%

TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

Agostino

Rooney

Herat

et al. 2021

IJMS

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Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.

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Protein–Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems

Cited by 16 publications

References 45 publications

Solvation Free Energy Calculations: The Combination between the Implicitly Polarized Fixed‐charge Model and the Reference Potential Strategy

Solvation Free Energy Calculations: The Combination between the Implicitly Polarized Fixed‐charge Model and the Reference Potential Strategy

Computational prediction of protein–protein binding affinities

TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

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