Modeling Ligand–Target Binding with Enhanced Sampling Simulations

Comitani, Federico; Gervasio, Francesco Luigi

doi:10.1002/9783527806836.ch3

Cited by 3 publications

(1 citation statement)

References 110 publications

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“…Many enhanced sampling methods have been developed and applied to free energy simulations, such as different variants of replica exchange methods including replica exchange with solute tempering, − grand canonical Monte Carlo, − Gaussian accelerated molecular dynamics, − weighted ensemble, − metadynamics, − orthogonal space tempering, − and expanded ensemble. − For more complete reviews, we refer the reader to refs – . Despite significant advancements in enhanced sampling methods, sufficient sampling of systems with buried charges in many cases remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering

Liu,

Brooks III

2024

J. Chem. Theory Comput.

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Buried ionizable groups in proteins often play important structural and functional roles. However, it is generally challenging to study the detailed molecular mechanisms solely based on experimental measurements. Free energy calculations using atomistic simulations, on the other hand, complement experimental studies and can provide high temporal and spatial resolution information that can lead to mechanistic insights. Nevertheless, it is also well recognized that sufficient sampling of such atomistic simulations can be challenging, considering that structural changes related to the buried charges may be very slow. In the present study, we describe a simple but effective enhanced sampling technique called replica exchange with charge tempering (REChgT) with a novel free energy method, multisite λ dynamics (MSλD), to study two systems containing buried charges, pK a prediction of a small molecule, orotate, in complex with the dihydroorotate dehydrogenase, and relative stability of a Glu–Lys pair buried in the hydrophobic core of two variants of Staphylococcal nuclease. Compared to the original MSλD simulations, the usage of REChgT dramatically increases sampling in both conformational and alchemical spaces, which directly translates into a significant reduction of wall time to converge the free energy calculations. This study highlights the importance of sufficient sampling toward developing improved free energy methods.

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Section: Introductionmentioning

confidence: 99%

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering

Liu,

Brooks III

2024

J. Chem. Theory Comput.

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Recent advances in computational and experimental protein-ligand affinity determination techniques

Kairys,

Baranauskiene,

Kazlauskiene

et al. 2024

Expert Opinion on Drug Discovery

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Analysis of metadynamics simulations by metadynminer.py

Beránek,

Křenek,

Spiwok

2024

Bioinformatics

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Motivation Molecular dynamics simulation is very useful but computationally demanding method of studying dynamics of biomolecular systems. Many enhanced sampling methods were developed in order to obtain the desired results in available computational time. Metadynamics and its variants are common enhanced sampling methods used for this purpose. Metadynamics simulations allow the user to gather large amounts of data, which have to be analyzed to elucidate the properties of the studied system. Results Here, we present metadynminer.py, a Python package that allows easy and user-friendly analysis and visualization of the results obtained from metadynamics simulations. The built-in functions automate frequent tasks and make the package easy to use for new users, while its many customization options and object-oriented nature allow for integration into specialized data analysis workflows by more advanced users. Availability The ‘metadynminer.py’ Python package is available under the GPL-3.0 license via PyPi and Conda. The development version is available on GitHub along with issue support (https://github.com/Jan8be/metadynminer.py). Documentation, tutorial and Jupyter Notebook (provided through the public mybinder.org service) are available at https://metadynreporter.cz.

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Modeling Ligand–Target Binding with Enhanced Sampling Simulations

Cited by 3 publications

References 110 publications

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering

Recent advances in computational and experimental protein-ligand affinity determination techniques

Analysis of metadynamics simulations by metadynminer.py

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