In silico studies of conformational dynamics of Mu opioid receptor performed using gaussian accelerated molecular dynamics

Liao, Jun-Min; Wang, Yeng‐Tseng

doi:10.1080/07391102.2017.1422025

Cited by 29 publications

(30 citation statements)

References 41 publications

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“…A GaMD method has been employed (Miao et al, 2015), adding a boost potential to the simulation that accelerates transitions between low-energy states (see section "Materials and Methods"). The method has been shown to enhance a broad sampling of the conformational space in large biomolecular systems McCammon, 2016, 2018;Wang and Chan, 2017;Liao and Wang, 2018;Sibener et al, 2018), including CRISPR-Cas9 as apo form and in complex with nucleic acids (Palermo et al, 2017;Palermo, 2019b), or bound to off-target DNAs (Ricci et al, 2019). Recently, GaMD has shown to sample long time scale motions in agreement with NMR relaxation experiments, showing that the method can efficiently capture the dynamics of large protein/nucleic acid complexes (East et al, 2020).…”

Section: Resultsmentioning

confidence: 96%

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Spontaneous Embedding of DNA Mismatches Within the RNA:DNA Hybrid of CRISPR-Cas9

Mitchell

Hsu

Medrano

et al. 2020

Front. Mol. Biosci.

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CRISPR-Cas9 is the forefront technology for editing the genome. In this system, the Cas9 protein is programmed with guide RNAs to process DNA sequences that match the guide RNA forming an RNA:DNA hybrid structure. However, the binding of DNA sequences that do not fully match the guide RNA can limit the applicability of CRISPR-Cas9 for genome editing, resulting in the so-called off-target effects. Here, molecular dynamics is used to probe the effect of DNA base pair mismatches within the RNA:DNA hybrid in CRISPR-Cas9. Molecular simulations revealed that the presence of mismatched pairs in the DNA at distal sites with respect to the Protospacer Adjacent Motif (PAM) recognition sequence induces an extended opening of the RNA:DNA hybrid, leading to novel interactions established by the unwound nucleic acids and the protein counterpart. On the contrary, mismatched pairs upstream of the RNA:DNA hybrid are rapidly incorporated within the heteroduplex, with minor effect on the protein-nucleic acid interactions. As a result, mismatched pairs at PAM distal ends interfere with the activation of the catalytic HNH domain, while mismatches fully embedded in the RNA:DNA do not affect the HNH dynamics and enable its activation to cleave the DNA. These findings provide a mechanistic understanding to the intriguing experimental evidence that PAM distal mismatches hamper a proper function of HNH, explaining also why mismatches within the heteroduplex are much more tolerated. This constitutes a step forward in understanding off-target effects in CRISPR-Cas9, which encourages novel structure-based engineering efforts aimed at preventing the onset of off-target effects.

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Section: Resultsmentioning

confidence: 96%

“…The method has extended the use of aMD to large biomolecular systems, with applications of this method to G-protein coupled receptors McCammon, 2016, 2018), the Mu opioid receptor (Wang and Chan, 2017;Liao and Wang, 2018), T-cell receptors (Sibener et al, 2018), and CRISPR-Cas9 (Palermo et al, 2017;Palermo, 2019b;Ricci et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

Spontaneous Embedding of DNA Mismatches Within the RNA:DNA Hybrid of CRISPR-Cas9

Mitchell

Hsu

Medrano

et al. 2020

Front. Mol. Biosci.

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“…One of the main advantages of GAMD compared to the related Accelerated Molecular Dynamics (AMD) technique (Hamelberg, Mongan, & McCammon, 2004) is that it allows free-energy calculations using reweighting that is often not possible in case of AMD due to energetic noise ( Miao et al, 2014( Miao et al, , 2015. The GAMD method has proven useful in modelling of drug-binding pathways to multiple targets , including G-protein coupled receptors (Liao & Wang, 2019;Miao, Bhattarai, Nguyen, Christopoulos, & May, 2018;Miao & McCammon, 2016) and the HIV protease (Miao, Huang, Walker, McCammon, & Chang, 2018). GAMD provides highly enhanced conformational sampling and has the potential to provide realistic ligand binding pathway as it does not depend on pre-defined reaction coordinates .…”

Section: Introductionmentioning

confidence: 99%

The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations

Balogh

Komáromi

Bereczky

2019

Journal of Biomolecular Structure and Dynamics

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The activity of antithrombin (AT), a serpin protease inhibitor, is enhanced by heparin and heparin analogs against its target proteases, mainly thrombin, factors Xa and IXa. Considerable amount of information is available on the multistep mechanism of the heparin pentasaccharide binding and conformational activation. However, much of the details were inferred from 'static' structures obtained by X-ray diffraction. Moreover, limited information is available for the early steps of binding mechanism other than kinetic studies with various ligands. To gain insights into these processes, we performed enhanced sampling molecular dynamics (MD) simulations using the Gaussian Accelerated Molecular Dynamics (GAMD) method, applied previously in drug binding studies. We were able to observe the binding of the pentasaccharide idraparinux to a 'non-activated' AT conformation in two separate trajectories with low root mean square deviation (RMSD) values compared to X-ray structures of the bound state. These trajectories along with further simulations of the AT-pentasaccharide complex provided insights into the mechanisms of multiple conformational transitions, including the expulsion of the hinge region, the extension of helix D and the conformational behavior of the reactive center loop (RCL). We could also confirm the high stability of helix P in non-activated AT conformations, such states might play an important role in heparin binding. 'Generalized correlation' matrices revealed possible paths of allosteric signal propagation to the binding sites for the target proteases, factors Xa and IXa. Enhanced MD simulations of ligand binding to AT may assist the design of new anticoagulant drugs.

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“…Moreover, because the boost potential exhibits a Gaussian distribution, biomolecular free energy profiles can be properly recovered through cumulant expansion to the second order [ 23 ]. GaMD simulations have successfully revealed mechanisms of protein folding and conformational changes [ 23 , 25 , 26 , 27 , 28 , 29 ], ligand binding [ 23 , 26 , 27 , 30 , 31 , 32 , 33 , 34 , 35 ], and protein-protein/membrane/nucleic acid interactions [ 32 , 36 , 37 , 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

Conrad

Söldner

Miao

et al. 2020

IJMS

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The histamine H2 receptor (H2R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H2R. Therefore, we created a model of the histamine-H2R-Gs complex based on the structure of the ternary complex of the β2-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H2R-Gs interface reveals a network of polar interactions that may contribute to H2R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a μs-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only Gs helix α5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs.

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In silico studies of conformational dynamics of Mu opioid receptor performed using gaussian accelerated molecular dynamics

Cited by 29 publications

References 41 publications

Spontaneous Embedding of DNA Mismatches Within the RNA:DNA Hybrid of CRISPR-Cas9

Spontaneous Embedding of DNA Mismatches Within the RNA:DNA Hybrid of CRISPR-Cas9

The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

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