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.

How low-resolution structural data predict the conformational changes of a protein: a study on data-driven molecular dynamics simulations

2018 ◽  
Vol 20 (26) ◽  
pp. 17790-17798 ◽  
Author(s):  
Ryuhei Harada ◽  
Yasuteru Shigeta
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Sampling Method ◽  
Protein A ◽  
Structural Data ◽  
Data Driven ◽  
Conformational Sampling ◽  
Transition Pathways ◽  
Dynamics Simulations

Parallel cascade selection molecular dynamics (PaCS-MD) is a conformational sampling method for generating transition pathways between a given reactant and a product.

scholarly journals An equilibrium constant pH molecular dynamics method for accurate prediction of pH-dependence in protein systems: Theory and application

2020 ◽  
Author(s):  
Ekaterina Kots ◽  
Derek M. Shore ◽  
Harel Weinstein
Keyword(s):  
Molecular Dynamics ◽  
Equilibrium Constant ◽  
Conformational Changes ◽  
Ph Dependence ◽  
Md Simulations ◽  
Water Soluble ◽  
Conformational Sampling ◽  
Ph Change ◽  
Constant Ph ◽  
Dynamics Simulations

ABSTRACTComputational modeling and simulation of biomolecular systems at their functional pH ranges requires an accurate approach to exploring the pH dependence of conformations and interactions. Here we present a new approach – the Equilibrium Constant pH (ECpH) method – to perform conformational sampling of protein systems in the framework of molecular dynamics simulations in an N, P, T-thermodynamic ensemble. The performance of ECpH is illustrated for two proteins with experimentally determined conformational responses to pH change: the small globular water-soluble bovine b-lactoglobulin (BBL), and the dimer transmembrane antiporter CLC-ec1 Cl−/H+. We show that with computational speeds comparable to equivalent canonical MD simulations we performed, the ECpH trajectories reproduce accurately the pH-dependent conformational changes observed experimentally in these two protein systems, some of which were not seen in the corresponding canonical MD simulations.Abstract FigureTable of Contents artwork

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.

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>

scholarly journals Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

2021 ◽  
Vol 22 (13) ◽  
pp. 6709
Author(s):  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Hong Chen ◽  
Ping Xie
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Binding Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Weak Interactions ◽  
Molecular Motor ◽  
Structural Data ◽  
Calculated Binding Energy ◽  
Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.

scholarly journals Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding

ACS Omega ◽  
2021 ◽  
Author(s):  
Yoshinori Hirano ◽  
Noriaki Okimoto ◽  
Shigeo Fujita ◽  
Makoto Taiji
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Binding Subsites
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