scholarly journals Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

2020 ◽  
Vol 60 (12) ◽  
pp. 6344-6354
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael O′Connor ◽  
Salomé Llabrés ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Protein Conformational Changes ◽  
Complex Protein

scholarly journals Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Protein Conformational Changes ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

scholarly journals Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Protein Conformational Changes ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

scholarly journals A Virtual Reality Ensemble Molecular Dynamics Workflow to Study Complex Conformational Changes in Proteins

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
A Priori ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

Coarse-Grained Molecular Dynamics Simulations of Sugar Transport Across Lactose Permease

2015 ◽  
Author(s):  
Yead Jewel ◽  
Prashanta Dutta ◽  
Jin Liu
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Active Transport ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Sugar Transport ◽  
Potential Of Mean Force ◽  
Coarse Grained ◽  
Lactose Permease ◽  
Protein Conformational Changes

Sugar (one of the critical nutrition elements for all life forms) transport across the cell membranes play essential roles in a wide range of living organism. One of the most important active transport (against the sugar concentration) mechanisms is facilitated by the transmembrane transporter proteins, such as the Escherichia coli lactose permease (LacY) proteins. Active transport of sugar molecules with LacY proteins requires a proton gradient and a sequence of complicated protein conformational changes. However, the exact molecular mechanisms and the protein structural information involved in the transport process are largely unknown. All atom atomistic simulations are able to provide full details but are limited to relative small length and time scales due to the computational cost. The protein conformational changes during sugar transport across LacY are large scale structural reorganization and inaccessible to all atom simulations. In this work, we investigate the molecular mechanisms and conformational changes during sugar transport using coarse-grained molecular dynamics (CGMD) simulations. In our coarse-grained force field, we follow the procedures developed by Han et al. [1, 2], in which the protein model is united-atom based and each heavy atom together with the attached hydrogen atoms is represented by one site, then the protein force filed is coupled with the MARTINI [3] water and lipid force fields. This hybrid force field takes the advantage of the efficiency of MARTINI force field for the environment (water and lipid), while retaining the detailed conformational information for the proteins. Specifically, we develop the new force fields for interactions between sugar molecules and protein by matching the potential of mean force between all-atom and coarse-grained models. Then we validate our force field by comparing the potential of mean force for a glucose interaction with a carbohydrate binding protein from our new force field, with the results from all atom simulations. After validation, we implement the force field for sugar transport across LacY proteins. Through our simulations we are able to capture the formation/breakage of the important hydrogen bonds and salt bridges, which are crucial to the overall conformational changes of LacY.

A Virtual Reality Environment for Interactive Molecular Dynamics Simulations of Complex Conformational Changes in Proteins

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
A Priori ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables a priori. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes for bioengineering efforts. </p>

scholarly journals Human Prion Protein Conformational Changes Susceptibility: A Molecular Dynamics Simulation Study

2014 ◽  
Vol 04 (04) ◽  
pp. 169-175 ◽  
Author(s):  
Laura Alejandra Mandujano-Rosas ◽  
Daniel Osorio-González ◽  
Pedro Guillermo Reyes-Romero ◽  
Jorge Mulia-Rodríguez
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Prion Protein ◽  
Conformational Changes ◽  
Simulation Study ◽  
Dynamics Simulation ◽  
Protein Conformational Changes ◽  
Human Prion Protein

Constant pH Molecular Dynamics Reveals How Proton Release Drives the Conformational Transition of a Transmembrane Efflux Pump

2017 ◽  
Author(s):  
Jana Shen ◽  
Zhi Yue ◽  
Helen Zgurskaya ◽  
Wei Chen
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Transmembrane Domain ◽  
Conformational Transition ◽  
Conformational Dynamics ◽  
Proton Release ◽  
Intrinsic Resistance ◽  
Constant Ph ◽  
Wide Range ◽  
Constant Ph Molecular Dynamics

AcrB is the inner-membrane transporter of E. coli AcrAB-TolC tripartite efflux complex, which plays a major role in the intrinsic resistance to clinically important antibiotics. AcrB pumps a wide range of toxic substrates by utilizing the proton gradient between periplasm and cytoplasm. Crystal structures of AcrB revealed three distinct conformational states of the transport cycle, substrate access, binding and extrusion, or loose (L), tight (T) and open (O) states. However, the specific residue(s) responsible for proton binding/release and the mechanism of proton-coupled conformational cycling remain controversial. Here we use the newly developed membrane hybrid-solvent continuous constant pH molecular dynamics technique to explore the protonation states and conformational dynamics of the transmembrane domain of AcrB. Simulations show that both Asp407 and Asp408 are deprotonated in the L/T states, while only Asp408 is protonated in the O state. Remarkably, release of a proton from Asp408 in the O state results in large conformational changes, such as the lateral and vertical movement of transmembrane helices as well as the salt-bridge formation between Asp408 and Lys940 and other sidechain rearrangements among essential residues.Consistent with the crystallographic differences between the O and L protomers, simulations offer dynamic details of how proton release drives the O-to-L transition in AcrB and address the controversy regarding the proton/drug stoichiometry. This work offers a significant step towards characterizing the complete cycle of proton-coupled drug transport in AcrB and further validates the membrane hybrid-solvent CpHMD technique for studies of proton-coupled transmembrane proteins which are currently poorly understood. <p><br></p>

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

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