scholarly journals Mechanism of electroneutral sodium/proton antiporter from transition-path shooting

2019 ◽  
Author(s):  
Kei-ichi Okazaki ◽  
David Wöhlert ◽  
Judith Warnau ◽  
Hendrik Jung ◽  
Özkan Yildiz ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Drug Target ◽  
Transition Path ◽  
Transition Path Sampling ◽  
Functional Homolog ◽  
Competing Demands ◽  
Transport Cycle ◽  
Ion Binding Sites ◽  
Pyrococcus Abyssi ◽  
Important Drug

Na+/H+ antiporters exchange sodium ions (Na+) and protons (H+) on opposite sides of lipid membranes, using the gradient of one ion to drive the uphill transport of the other. The electroneutral Na+/H+ antiporter NhaP from archaea Pyrococcus abyssi (PaNhaP) is a functional homolog of the human Na+/H+ exchanger NHE1, which is an important drug target. Here we resolve the Na+ and H+ transport cycle of PaNhaP in continuous and unbiased molecular dynamics trajectories that cover the entire transport cycle. We overcome the enormous time-scale gap between seconds-scale ion exchange and microseconds simulations by transition-path shooting. In this way, we selectively capture the rare events in which the six-helix-bundle transporter domain spontaneously moves up and down to shuttle protons and ions across the membrane. The simulations reveal two hydrophobic gates above and below the ion-binding sites that open and close in response to the bundle motion. Weakening the outside gate by mutagenesis makes the transporter faster, suggesting that the gate balances competing demands of fidelity and efficiency. Transition-path sampling and a committor-based reaction coordinate optimization identify the essential motions and interactions that realize conformational alternation between the two access states in transporter function.

Rare event simulation

2017 ◽  
Author(s):  
Michael P. Allen ◽  
Dominic J. Tildesley
Keyword(s):  
Rare Event ◽  
Path Sampling ◽  
Rapid Progress ◽  
Computationally Efficient ◽  
Transition Path ◽  
Transition Path Sampling ◽  
Event Simulation ◽  
Reaction Coordinates ◽  
Simulation Techniques ◽  
Transition Interface

The development of techniques to simulate infrequent events has been an area of rapid progress in recent years. In this chapter, we shall discuss some of the simulation techniques developed to study the dynamics of rare events. A basic summary of the statistical mechanics of barrier crossing is followed by a discussion of approaches based on the identification of reaction coordinates, and those which seek to avoid prior assumptions about the transition path. The demanding technique of transition path sampling is introduced and forward flux sampling and transition interface sampling are considered as rigorous but computationally efficient approaches.

scholarly journals Catalytic Mechanism of Processive GlfT2: Transition Path Sampling Investigation of Substrate Translocation

ACS Omega ◽  
2020 ◽  
Vol 5 (34) ◽  
pp. 21374-21384
Author(s):  
Pavel Janoš ◽  
Igor Tvaroška ◽  
Christoph Dellago ◽  
Jaroslav Koča
Keyword(s):  
Catalytic Mechanism ◽  
Path Sampling ◽  
Transition Path ◽  
Transition Path Sampling

Understanding rare safety and reliability events using transition path sampling

2018 ◽  
Vol 108 ◽  
pp. 74-88 ◽  
Author(s):  
Ian H. Moskowitz ◽  
Warren D. Seider ◽  
Amish J. Patel ◽  
Jeffrey E. Arbogast ◽  
Ulku G. Oktem
Keyword(s):  
Path Sampling ◽  
Transition Path ◽  
Transition Path Sampling ◽  
Safety And Reliability

scholarly journals Residue-Residue Mutual Work Analysis of Retinal-Opsin Interaction in Rhodopsin: Implications for Protein-Ligand Binding

2019 ◽  
Author(s):  
Wenjin Li
Keyword(s):  
Virtual Work ◽  
Interaction Matrix ◽  
Time Interval ◽  
Transition Path ◽  
Transition Path Sampling ◽  
Decomposition Approach ◽  
Work Analysis ◽  
Nmr Study ◽  
The Matrix ◽  
Dynamics Simulations

AbstractEnergetic contributions at single-residue level to retinal-opsin interaction in rhodopsin were studied by combining molecular dynamics simulations, transition path sampling, and a newly developed energy decomposition approach. The virtual work at an infinitesimal time interval was decomposed into the work components on one residue due to its interaction with another residue, which were then averaged over the transition path ensemble along a proposed reaction coordinate. Such residue-residue mutual work analysis on 62 residues within the active center of rhodopsin resulted in a very sparse interaction matrix, which is generally not symmetric but anti-symmetric to some extent. 14 residues were identified to be major players in retinal relaxation, which is in excellent agreement with an existing NMR study. Based on the matrix of mutual work, a comprehensive network was constructed to provide detailed insights into the chromophore-protein interaction from a viewpoint of energy flow.

scholarly journals Inverse enzyme isotope effects in human purine nucleoside phosphorylase with heavy asparagine labels

2018 ◽  
Vol 115 (27) ◽  
pp. E6209-E6216 ◽  
Author(s):  
Rajesh K. Harijan ◽  
Ioanna Zoi ◽  
Dimitri Antoniou ◽  
Steven D. Schwartz ◽  
Vern L. Schramm
Keyword(s):  
Transition State ◽  
Purine Nucleoside Phosphorylase ◽  
Isotope Effects ◽  
Catalytic Site ◽  
Path Sampling ◽  
Transition Path ◽  
Transition Path Sampling ◽  
Steady State Kinetics ◽  
Leaving Group ◽  
Transition State Barrier

Transition path-sampling calculations with several enzymes have indicated that local catalytic site femtosecond motions are linked to transition state barrier crossing. Experimentally, femtosecond motions can be perturbed by labeling the protein with amino acids containing 13C, 15N, and nonexchangeable 2H. A slowed chemical step at the catalytic site with variable effects on steady-state kinetics is usually observed for heavy enzymes. Heavy human purine nucleoside phosphorylase (PNP) is slowed significantly (kchemlight/kchemheavy = 1.36). An asparagine (Asn243) at the catalytic site is involved in purine leaving-group activation in the PNP catalytic mechanism. In a PNP produced with isotopically heavy asparagines, the chemical step is faster (kchemlight/kchemheavy = 0.78). When all amino acids in PNP are heavy except for the asparagines, the chemical step is also faster (kchemlight/kchemheavy = 0.71). Substrate-trapping experiments provided independent confirmation of improved catalysis in these constructs. Transition path-sampling analysis of these partially labeled PNPs indicate altered femtosecond catalytic site motions with improved Asn243 interactions to the purine leaving group. Altered transition state barrier recrossing has been proposed as an explanation for heavy-PNP isotope effects but is incompatible with these isotope effects. Rate-limiting product release governs steady-state kinetics in this enzyme, and kinetic constants were unaffected in the labeled PNPs. The study suggests that mass-constrained femtosecond motions at the catalytic site of PNP can improve transition state barrier crossing by more frequent sampling of essential catalytic site contacts.

scholarly journals Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

2020 ◽  
Vol 21 (18) ◽  
pp. 6654
Author(s):  
Stephen Safe ◽  
Un-ho Jin ◽  
Hyejin Park ◽  
Robert S. Chapkin ◽  
Arul Jayaraman
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Drug Target ◽  
Tissue Cell ◽  
Intracellular Protein ◽  
Aryl Hydrocarbon ◽  
Agonist And Antagonist ◽  
Type Mutant ◽  
Receptor Modulators ◽  
Important Drug

The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.

scholarly journals Atomistic insight into the kinetic pathways for Watson–Crick to Hoogsteen transitions in DNA

2019 ◽  
Vol 47 (21) ◽  
pp. 11069-11076 ◽  
Author(s):  
Jocelyne Vreede ◽  
Alberto Pérez de Alba Ortíz ◽  
Peter G Bolhuis ◽  
David W H Swenson
Keyword(s):  
Double Helix ◽  
Path Sampling ◽  
Important Process ◽  
Free Energies ◽  
Transition Path ◽  
Base Pairs ◽  
Transition Path Sampling ◽  
Insight Into ◽  
Adenine Base ◽  
Transition Interface

Abstract DNA predominantly contains Watson–Crick (WC) base pairs, but a non-negligible fraction of base pairs are in the Hoogsteen (HG) hydrogen bonding motif at any time. In HG, the purine is rotated ∼180° relative to the WC motif. The transitions between WC and HG may play a role in recognition and replication, but are difficult to investigate experimentally because they occur quickly, but only rarely. To gain insight into the mechanisms for this process, we performed transition path sampling simulations on a model nucleotide sequence in which an AT pair changes from WC to HG. This transition can occur in two ways, both starting with loss of hydrogen bonds in the base pair, followed by rotation around the glycosidic bond. In one route the adenine base converts from WC to HG geometry while remaining entirely within the double helix. The other route involves the adenine leaving the confines of the double helix and interacting with water. Our results indicate that this outside route is more probable. We used transition interface sampling to compute rate constants and relative free energies for the transitions between WC and HG. Our results agree with experiments, and provide highly detailed insights into the mechanisms of this important process.

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