Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study

Wang, Lingyun; Yan, Feng

doi:10.1002/pro.3239

Cited by 9 publications

(3 citation statements)

References 55 publications

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“…The binding free energy was calculated using the molecular mechanics/generalized Born surface area (MM/GBSA) approach . The calculation procedure is similar to our previous work. − In brief, the binding free energy (Δ G binding ) was computed by summing the molecular mechanics energy including the electrostatic energy (Δ E ele ) and the van der Waals energy (Δ E vdW ), the solvation free energy including a polar part (Δ G pol ) and a nonpolar part (Δ G nonpol ), and the entropy contribution to the binding (− T Δ S ). To determine which residue of AT 1 R plays an important role in the binding of VST, the interaction energy was calculated by decomposing the binding free energy based on each residue of the receptor.…”

Section: Methodsmentioning

confidence: 99%

Trans and Cis Conformations of the Antihypertensive Drug Valsartan Respectively Lock the Inactive and Active-like States of Angiotensin II Type 1 Receptor: A Molecular Dynamics Study

Wang

Yan

2018

J. Chem. Inf. Model.

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Angiotensin II type 1 receptor (ATR) is the principal regulator of blood pressure in humans. The overactivation of ATR by the stimulation of angiotensin II would result in high blood pressure. To prevent hypertension, nonpeptide "sartan" drugs, such as valsartan (VST), have been developed to competitively block the access of angiotensin II to the receptor. Nuclear magnetic resonance spectroscopy and molecular modeling studies have identified that VST in solution and in lipid micelles (a mimic membrane environment) has two distinct trans/cis conformations (VST/VST) that can be transformed into each other through the isomerization of the amide bond. To date, it is still not known whether the two conformations of VST can affect the binding of ATR with VST. To this end, the binding of ATR with VST or VST was modeled based on the recently determined crystal structures of ATR. Molecular dynamics simulations were then performed to study the structural and dynamical differences of ATR caused by the two conformations of VST. Simulation results show that ATR with VST has higher structural and dynamical stabilities compared to that with VST. Binding energy analysis indicates that ATR bind more strongly with VST, and the energy difference mainly results from the contribution of van der Waals and nonpolar interactions. Detailed analyses reveal that unlike ATR with VST, ATR with VST displays an activate-like state, which is characterized by a small outward movement of transmembrane helix 6. Due to the altered interaction with the butyl group of VST, residue Tyr87 undergoes a conformational change that causes a contraction of the pocket for VST binding. The rearrangement of ATR is then propagated to the intracellular side of the receptor through the conformational change of residue Trp253 (the toggle switch), which results in an expansion of the pocket for G protein binding and the breakage of the hydrogen bond containing the conserved residue Arg126. These data provide insights into the activation mechanism of ATR caused by the binding of VST, which may help to design a new drug to inhibit ATR and prevent high blood pressure.

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Section: Methodsmentioning

confidence: 99%

Trans and Cis Conformations of the Antihypertensive Drug Valsartan Respectively Lock the Inactive and Active-like States of Angiotensin II Type 1 Receptor: A Molecular Dynamics Study

Wang

Yan

2018

J. Chem. Inf. Model.

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“…Consequently, the optimized positions of Asp 274 , Arg 400 , and Arg 275 diverged significantly from their native PP5/phosphate co-crystal positions. It should be added that a molecular dynamics (MD) study of PP5/phosphoserine by Wang and Yan [19] concluded that W 1 (OH − )-based systems are stable, while W 1 (H 2 O)-based systems are not, in further support of the conclusion that W 1 is a hydroxide. Additionally, they found that the W 1 (OH − )/W 2 (H 2 O) system has greater substrate affinity versus the W 1 (OH − )/W 2 (OH − ) system.…”

Section: Introductionmentioning

confidence: 94%

Quantum-Based Modeling of Dephosphorylation in the Catalytic Site of Serine/Threonine Protein Phosphatase-5 (PPP5C)

2020

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Serine/threonine protein phosphatase-5 (PP5; PPP5C) is a member of the phosphoprotein phosphatase (PPP) gene family. The PPP catalytic domains feature a bimetal system (M1/M2), an associated bridge hydroxide (W1(OH−)), an M1-bound water/hydroxide (W2), and a highly conserved core sequence. The PPPs are presumed to share a common mechanism: The seryl/threonyl phosphoryl group of the phosphoprotein coordinates the metal ions, W1(OH−) attacks the central phosphorous atom, rupturing the antipodal phosphoester bond and releasing the phosphate-free protein. Also, a histidine/aspartate tandem is responsible for protonating the exiting seryl/threonyl alkoxide. Here, we employed quantum-based computations on a large section of the PP5 catalytic site. A 33-residue, ONIOM(UB3LYP/6-31G(d):UPM7) model was built to perform computations using methylphosphate dianion as a stand-in substrate for phosphoserine/phosphothreonine. We present a concerted transition state (TS) in which W1(OH−) attacks the phosphate center at the same time that the exiting seryl/threonyl alkoxide is protonated directly by the His304/Asp274 tandem, with W2 assigned as a water molecule: W2(H2O). Arg275, proximal to M1, stabilizes the substrate and TS by binding both the ester oxygen (Oγ) and a phosphoryl oxygen (O1) in a bidentate fashion; in the product state, Tyr451 aids in decoupling Arg275 from O1 of the product phosphate ion. The reaction is exothermic (ΔH = −2.0 kcal/mol), occurs in a single step, and has a low activation barrier (ΔH‡ = +10.0 kcal/mol). Our work is an improvement over an earlier computational study that also found bond rupture and alkoxide protonation to be concerted, but concluded that Arg275 is deprotonated during the reactant and TS stages of the pathway. In that earlier study, the critical electron-withdrawal role that Arg275 plays during the hydroxide attack was not correctly accounted for.

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“…Although only the open-cubane is observed by XFEL crystallography, the interpretation of XFEL data remains debatable, − with the oxidation state of Mn in XFEL studies highly questioned and a mixture of different populations at one snapshot not resolved . Therefore, the existence of the closed-cubane isomer and its use to insert the sixth ligand cannot be ruled out.…”

Section: Introductionmentioning

confidence: 99%

Water Ligands Regulate the Redox Leveling Mechanism of the Oxygen-Evolving Complex of the Photosystem II

Liu,

Yang,

Long

et al. 2024

J. Am. Chem. Soc.

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Understanding how water ligands regulate the conformational changes and functionality of the oxygen-evolving complex (OEC) in photosystem II (PSII) throughout the catalytic cycle of oxygen evolution remains a highly intriguing and unresolved challenge. In this study, we investigate the effect of water insertion (WI) on the redox state of the OEC by using the molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) hybrid methods. We find that water binding significantly reduces the free energy change for proton-coupled electron transfer (PCET) from Mn to Y Z• , underscoring the important regulatory role of water binding, which is essential for enabling the OEC redox-leveling mechanism along the catalytic cycle. We propose a water binding mechanism in which WI is thermodynamically favored by the closed-cubane form of the OEC, with water delivery mediated by Ca 2+ ligand exchange. Isomerization from the closed-to open-cubane conformation at three post-WI states highlights the importance of the location of the Mn III center in the OEC and the orientation of its Jahn−Teller axis to conformational changes of the OEC, which might be critical for the formation of the O−O bond. These findings reveal a complex interplay between conformational changes in the OEC and the ligand environment during the activation of the OEC by Y Z •. Analogous regulatory effects due to water ligand binding are expected to be important for a wide range of catalysts activated by redox state transitions in aqueous environments.

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Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study

Cited by 9 publications

References 55 publications

Trans and Cis Conformations of the Antihypertensive Drug Valsartan Respectively Lock the Inactive and Active-like States of Angiotensin II Type 1 Receptor: A Molecular Dynamics Study

Trans and Cis Conformations of the Antihypertensive Drug Valsartan Respectively Lock the Inactive and Active-like States of Angiotensin II Type 1 Receptor: A Molecular Dynamics Study

Quantum-Based Modeling of Dephosphorylation in the Catalytic Site of Serine/Threonine Protein Phosphatase-5 (PPP5C)

Water Ligands Regulate the Redox Leveling Mechanism of the Oxygen-Evolving Complex of the Photosystem II

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