Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations

Metallomics ◽  
2021 ◽  
Author(s):  
Catarina Pimpão ◽  
Darren Wragg ◽  
Riccardo Bonsignore ◽  
Brech Aikman ◽  
Per Amstrup Pedersen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Global Change ◽  
Conformational Changes ◽  
Organometallic Complexes ◽  
Atomistic Simulations ◽  
Stopped Flow ◽  
Computational Results ◽  
Functional Assays ◽  
N Compounds

Abstract The inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes has been studied by fluorescence stopped-flow spectroscopy, and its mechanism has been described using molecular modelling and atomistic simulations. The most effective hAQP10 inhibitors are cyclometalated Au(III) C^N compounds known to efficiently react with cysteine residues leading to the formation of irreversible C—S bonds. Functional assays also demonstrate the irreversibility of the binding to hAQP10 by the organometallic complexes. The obtained computational results by metadynamics show that the local arylation of Cys209 in hAQP10 by one of the gold inhibitors is mapped into a global change of the overall free energy of glycerol translocation across the channel. Our study further pinpoints the need to understand the mechanism of glycerol and small molecule permeation as a combination of local structural motifs and global pore conformational changes, which are taking place on the scale of the translocation process and whose study therefore, require sophisticated molecular dynamics strategies.

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 Thermodynamic coupling between activation and inactivation gating in potassium channels revealed by free energy molecular dynamics simulations

2011 ◽  
Vol 138 (6) ◽  
pp. 571-580 ◽  
Author(s):  
Albert C. Pan ◽  
Luis G. Cuello ◽  
Eduardo Perozo ◽  
Benoît Roux
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Ionic Current ◽  
Selectivity Filter ◽  
Recent Analysis ◽  
Steric Interaction ◽  
Inactivation Gating ◽  
Dynamics Simulations

The amount of ionic current flowing through K+ channels is determined by the interplay between two separate time-dependent processes: activation and inactivation gating. Activation is concerned with the stimulus-dependent opening of the main intracellular gate, whereas inactivation is a spontaneous conformational transition of the selectivity filter toward a nonconductive state occurring on a variety of timescales. A recent analysis of multiple x-ray structures of open and partially open KcsA channels revealed the mechanism by which movements of the inner activation gate, formed by the inner helices from the four subunits of the pore domain, bias the conformational changes at the selectivity filter toward a nonconductive inactivated state. This analysis highlighted the important role of Phe103, a residue located along the inner helix, near the hinge position associated with the opening of the intracellular gate. In the present study, we use free energy perturbation molecular dynamics simulations (FEP/MD) to quantitatively elucidate the thermodynamic basis for the coupling between the intracellular gate and the selectivity filter. The results of the FEP/MD calculations are in good agreement with experiments, and further analysis of the repulsive, van der Waals dispersive, and electrostatic free energy contributions reveals that the energetic basis underlying the absence of inactivation in the F103A mutation in KcsA is the absence of the unfavorable steric interaction occurring with the large Ile100 side chain in a neighboring subunit when the intracellular gate is open and the selectivity filter is in a conductive conformation. Macroscopic current analysis shows that the I100A mutant indeed relieves inactivation in KcsA, but to a lesser extent than the F103A mutant.

scholarly journals Computational Investigations on Interactions Between DNA and Flavonols

2021 ◽  
Vol 12 (6) ◽  
pp. 8117-8127
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Side Effects ◽  
Free Energy Calculations ◽  
Main Task ◽  
Computational Results ◽  
Ligand Complex ◽  
Drug Designing

Today, the main task of researchers is to study and develop drugs that are less toxic and have lesser side effects. The principal motive of this research is to study and analyze the interaction between naturally active compounds flavonoids with biomolecule DNA. Since the interaction between DNA and ligand is essential in drug designing, this study will provide a good base for further research and development of less toxic and more efficient drugs for various diseases. The selected compounds for this study are Kaempferide, Kaempferol, Morin, and Rutin. They all fall into the category ‘flavonols’ of flavonoids. Computational methods are implemented for theoretical drug designing. These are molecular optimization, molecular docking, and molecular dynamics. Computational results are compared with experimental data from previous studies. Molecular docking gives the most preferred orientation of ligands within DNA, and Molecular Dynamics provides the details about the DNA-ligand complex with respect to time. Free energy calculations were also performed by implementing MMPBSA and MMGBSA calculations.

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 A Free-Energy Landscape Analysis of Calmodulin Obtained from an NMR Data-Utilized Multi-Scale Divide-and-Conquer Molecular Dynamics Simulation

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1241
Author(s):  
Hiromitsu Shimoyama ◽  
Yasuteru Shigeta
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Structural Change ◽  
Conformational Changes ◽  
Calcium Binding ◽  
Structural Changes ◽  
Energy Landscape ◽  
Divide And Conquer ◽  
Free Energy Landscape ◽  
Multi Scale

Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon calcium binding, the N-lobe and C-lobe undergo local conformational changes, followed by a major conformational change of the entire CaM to wrap the target enzyme. However, the regulation mechanisms, such as allosteric interactions, which regulate the large structural changes, are still unclear. In order to investigate the series of structural changes, the free-energy landscape of CaM was obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD). The resultant free-energy landscape (FEL) shows that the Ca2+ bound CaM (holo-CaM) would take an experimentally famous elongated structure, which can be formed in the early stage of structural change, by breaking the inter-domain interactions. The FEL also shows that important interactions complete the structural change from the elongated structure to the ring-like structure. In addition, the FEL might give a guiding principle to predict mutational sites in CaM. In this study, it was demonstrated that the movement process of macroscopic variables on the FEL may be diffusive to some extent, and then, the MSDC-MD is suitable to the parallel computation.

Computational insight into the anticholinesterase activities and electronic properties of physostigmine analogs

2019 ◽  
Vol 11 (15) ◽  
pp. 1907-1928 ◽  
Author(s):  
Adebayo A Adeniyi ◽  
Jeanet Conradie
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Quantum Mechanics ◽  
Structural Properties ◽  
Conformational Changes ◽  
Energy Surface ◽  
Binding Free Energy ◽  
The Elderly ◽  
Free Energy Surface ◽  
Insight Into

Aim: Alzheimer's disease (AD) is known to be themajor cause of dementia among the elderly. The structural properties and binding interactions of the AD drug physostigmine (-)-phy, and its analogues (-)-hex and (-)-phe and (+)-phe, were examined, as well as their impact on the conformational changes of two different AD target enzymes AChE and BChE. Materials & methods: The conformational changes were studied using molecular dynamics and structural properties using Quantum mechanics. Results & conclusions: The binding free energy (ΔGbind) and the change in the free energy surface (FES) computed from the funnel metadynamics (FMD) simulation, both support the idea that inhibitors (-)-phe and (-)-hex have better binding activities toward enzyme AChE, and that (-)-phe is stronger in binding than the present AD drug (-)-phy.

scholarly journals Evaluating the accuracy of the umbrella sampling plots with different dissociation paths, conformational changes, and structure preparation

2017 ◽  
Author(s):  
Wanli You ◽  
Zhiye Tang ◽  
Chia-en A. Chang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Conformational Changes ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Conformational Space ◽  
Drug Candidate ◽  
Energy Calculation ◽  
Dissociation Pathway ◽  
Collective Variables

AbstractThe kinetics of ligand dissociation has been found to be crucial for a good drug candidate. Therefore, examining the underlying free energy profile of the dissociation that governs the kinetics becomes important. Umbrella sampling (US), a widely used free energy calculation method, has long been used to explore the dissociation process of ligand-receptor systems. The potential of mean force (PMF) computed from US seems to always produce binding affinity and energy barriers that more or less agree with experiments. However, such PMFs are influenced by many practical aspects, like the method used to generate the initial dissociation pathway, collective variables (CVs) that used to describe the reaction coordinate (RC), and how intensive the sampling is in the conformational space restrained by the CVs. These critical factors were rarely studied. Here we applied US to study the dissociation processes of β-cyclodextrin (β-CD) and p38α complex systems. For β-CD, we used three different β-CD conformations to generate the dissociation path manually. For p38α, we generated the dissociation pathway using accelerated molecular dynamics (AMD) followed by conformational relaxing with short conventional molecular dynamics (MD), steered molecular dynamics (SMD) and manual pulling. We found that even for small β-CD complexes, different β-CD conformations will alter the height of the PMF and different dissociation directions result in appearance/disappearance of local minima. SMD poorly samples the residue sidechain movement, leading to overestimated height of PMF. On the other hand, the AMD pathway relaxed by short conventional MD sampled more accurate structures, resulting in reasonable PMF.

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