Are induced fit protein conformational changes caused by ligand-binding predictable? A molecular dynamics investigation

2017 ◽  
Vol 38 (15) ◽  
pp. 1229-1237 ◽  
Author(s):  
Cen Gao ◽  
Jeremy Desaphy ◽  
Michal Vieth
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Induced Fit ◽  
Protein Conformational Changes

scholarly journals Induced fit for cytochrome P450 3A4 based on molecular dynamics

ADMET & DMPK ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 252-266
Author(s):  
Thomas R.F. Scior ◽  
Israel Quiroga
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Strain Energy ◽  
Crystal Form ◽  
Conformational Sampling ◽  
Cytochrome P450 3A4 ◽  
Induced Fit ◽  
Dynamics Simulations ◽  
Enzyme Complexes

The present study aims at numerically describing to what extent substrate - enzyme complexes in solution may change over time as a natural process of conformational changes for a liganded enzyme in comparison to those movements which occur independently from substrate interaction, i.e. without a ligand. To this end, we selected structurally known pairs of liganded / unliganded CYP450 3A4 enzymes with different geometries hinting at induced fit events. We carried out molecular dynamics simulations (MD) comparing the trajectories in a “cross-over” protocol: (i) we added the ligand to the unliganded crystal form which should adopt geometries similar to the known geometry of the liganded crystal structure during MD, and – conversely – (ii) we removed the bound ligand form the known liganded complex to test if a geometry similar to the known unliganded (apo-) form can be adopted during MD. To compare continues changes we measured root means square deviations and frequencies. Results for case (i) hint at larger conformational changes required for accepting the substrate during its approach to final position – in contrast to case (ii) when mobility is fairly reduced by ligand binding (strain energy). In conclusion, a larger conformational sampling prior to ligand binding and the freezing-in (rigidity) of conformations for bound ligands can be interpreted as two conditions linked to induced-fit.

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 ◽  
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 Binding mechanism and dynamic conformational change of C subunit of PKA with different pathways

2017 ◽  
Vol 114 (38) ◽  
pp. E7959-E7968 ◽  
Author(s):  
Wen-Ting Chu ◽  
Xiakun Chu ◽  
Jin Wang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Conformational Change ◽  
Conformational Changes ◽  
Coarse Grained ◽  
Binding Mechanism ◽  
Induced Fit ◽  
C Subunit ◽  
Dynamics Simulations ◽  
Substrate Inhibitor

The catalytic subunit of PKA (PKAc) exhibits three major conformational states (open, intermediate, and closed) during the biocatalysis process. Both ATP and substrate/inhibitor can effectively induce the conformational changes of PKAc from open to closed states. Aiming to explore the mechanism of this allosteric regulation, we developed a coarse-grained model and analyzed the dynamics of conformational changes of PKAc during binding by performing molecular dynamics simulations forapoPKAc, binary PKAc (PKAc with ATP, PKAc with PKI), and ternary PKAc (PKAc with ATP and PKI). Our results suggest a mixed binding mechanism of induced fit and conformational selection, with the induced fit dominant. The ligands can drive the movements of Gly-rich loop as well as some regions distal to the active site in PKAc and stabilize them at complex state. In addition, there are two parallel pathways (pathway with PKAc-ATP as an intermediate and pathway PKAc-PKI as an intermediate) during the transition from open to closed states. By molecular dynamics simulations and rate constant analyses, we find that the pathway through PKAc-ATP intermediate is the main binding route from open to closed state because of the fact that the bound PKI will hamper ATP from successful binding and significantly increase the barrier for the second binding subprocess. These findings will provide fundamental insights of the mechanisms of PKAc conformational change upon binding.

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