Exploring ligand binding pathways on proteins using hypersound–accelerated molecular dynamics

Araki, Mitsugu; Matsumoto, Shigeyuki; Bekker, Gert‐Jan; Isaka, Yuta; Sagae, Yukari; Kamiya, Narutoshi; Okuno, Yasushi

doi:10.21203/rs.3.rs-149745/v1

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…In this approach, the values of the degrees of freedom of a system are changed randomly rather than systematically like in stochastic algorithms [41]. The speed of these procedures is beneficial, as they might potentially locate the best answer very quickly.…”

Section: Semi-flexible Docking Algorithm With Stochastic Methodsmentioning

confidence: 99%

Molecular Docking in the Study of Ligand-Protein Recognition: An Overview

Azad¹

2023

Biomedical Engineering

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Molecular docking is a bioinformatics-based theoretical simulation strategy. It is employed to study ligand-protein interaction profiles and predict their binding conformers and affinity through computational tools. Since the 1980s, computational tools have been used in the drug discovery process. The initial molecular modeling approaches available at the time focused on a rigid view of the ligand-protein interaction due to the limited computational capabilities. The advancement of hardware technology has made it possible to simulate the dynamic character of the ligand-protein interactions throughout time. The current chapter deals with an outline of the progression of structure-based drug discovery methodologies in the investigation of the ligand-protein interaction profiles from static to improved molecular docking strategies.

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Section: Semi-flexible Docking Algorithm With Stochastic Methodsmentioning

confidence: 99%

Molecular Docking in the Study of Ligand-Protein Recognition: An Overview

Azad¹

2023

Biomedical Engineering

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“…However, true observation of thermodynamic equilibrium can only be achieved with an ensemble of molecules, while simulation usually studies one complex. A ligand unbound from its pocket will be very unlikely to rebind in simulation, and when it does the unbound/bound population or time does not reflect any real K. 11,12 So here in this study it is by no means relying on the observation of equilibrium shift of our ternary poses.…”

Section: Introductionmentioning

confidence: 99%

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

Liao

Nie

Unarta

et al. 2021

Preprint

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Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that can induce the ubiquitination of targeted proteins via the formation of ternary complexes between an E3 ubiquitin ligase and a target protein. The poly-ubiquitinated target protein will be escorted to the proteasome for degradation. Rational design of PROTACs require knowledge of an accurate configuration of the PROTAC induced ternary complex. This study demonstrates that native ternary poses can be distinguished by scoring candidate poses based on the pose residence time. The scoring is essentially heat-and-dissociate trials of candidate poses sampled by MD and pre-ranked by the classic MM/GBSA method. It is practical, simple to use and self-intuitive, relying on the observation that the assumed more stable native crystal ternary poses maintained a longer residence time than non-native ones at both room and higher temperatures. A time score and temperature score were generated from multiple replicate trajectories. These scores were able to correctly identify the native pose from non-native ones in all the systems examined. The absolute numbers were comparable across different systems in all currently available VHL and CRBN-containing ternary crystal structures. Therefore, it is also possible to provide an empirical criteria for unresolved ternary structures that under the conditions of this study. If a ternary pose is stable up to over a certain threshold score, it is likely a native pose. The success of the method is in part attributed to the dynamic nature of the pose change analysis which naturally involves entropic effects, one that is intrinsically unavailable with faster static scoring methods that consider molecular mechanical energy only. Protein-protein binding entropy is much more significant than in protein-ligands binding. The success is also attributed to the fact that the protein structures themselves were all stable in the short heating trials.

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“…However, true observation of thermodynamic equilibrium can only be achieved with an ensemble of molecules, while simulation usually studies one complex. A ligand unbound from its pocket will be unlikely to rebind in simulation, and when it does, to the best of our knowledge there are so far no reports on any protein-ligand system of any size for which it was possible to use the unbound/bound population or time to obtain equilibrium K. [11][12][13][14][15] Thus, this study is by no means relying on or attempting to observe equilibrium shift of the ternary poses.…”

Section: Introductionmentioning

confidence: 99%

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

Liao

Nie

Unarta

et al. 2021

Preprint

View full text Add to dashboard Cite

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and subsequent degradation of proteins via formation of ternary complexes between an E3 ubiquitin ligase and a target protein. Rational design of PROTACs requires accurate knowledge of the native configuration of the PROTAC induced ternary complex. This study demonstrates that native and non-native ternary complex poses can be distinguished based on pose occupancy time in MD, where native poses exhibit longer occupancy times than non-native ones at both room and higher temperatures. Candidate poses are generated by MD sampling and pre-ranked by the classic MM/GBSA method. A specific heating scheme is then applied to induce ternary pose departure, generating an occupancy score and temperature score reflecting pose occupancy time and fraction. The scoring approach enables identification of the native pose in all the test systems. Beyond providing a relative rank of hypothetical poses of a given ternary system, the method could also provide empirical guidance to whether a given ternary pose is likely a native one or not. The success of the method is in part attributed to the dynamic nature of the pose departure analysis which accounts for solute entropic effects, typically neglected in the faster static pose scoring methods, while solute entropic contributions play a greater role in protein-protein interactions than in protein-ligand systems.

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Exploring ligand binding pathways on proteins using hypersound–accelerated molecular dynamics

Cited by 4 publications

References 24 publications

Molecular Docking in the Study of Ligand-Protein Recognition: An Overview

Molecular Docking in the Study of Ligand-Protein Recognition: An Overview

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

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