Constant-pH Molecular Dynamics with Ionic Strength Effects:  Protonation−Conformation Coupling in Decalysine

Machuqueiro, Miguel; Baptista, António M.

doi:10.1021/jp056456q

Cited by 114 publications

(230 citation statements)

References 60 publications

(112 reference statements)

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“…In this work, we use the implementation for the GROMACS package of the stochastic titration method developed by us [29,33,[36][37][38][39]. This method consists essentially of a molecular mechanics/dynamics (MM/MD) simulation with explicit solvent in which the protonation states of the protein are periodically replaced with new states obtained from a Poisson-Boltzmann (PB) and Monte Carlo (MC) calculation, being composed of three sequential blocks that are cyclically repeated [29] (see Figure S4).…”

Section: Constant-ph MD Simulationsmentioning

confidence: 99%

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Coupling between protonation and conformation in cytochrome c oxidase: Insights from constant-pH MD simulations

Oliveira¹,

Campos²,

Baptista³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Cytochrome c oxidases (CcOs) are the terminal enzymes of the respiratory chain in mitochondria and most bacteria. These enzymes reduce dioxygen (O(2)) to water and, simultaneously, generate a transmembrane electrochemical proton gradient. Despite their importance in the aerobic metabolism and the large amount of structural and biochemical data available for the A1-type CcO family, there is still no consensually accepted description of the molecular mechanisms operating in this protein. A substantial number of questions about the CcO's working mechanism remain to be answered, including how the protonation behavior of some key residues is modulated during a reduction cycle and how is the conformation of the protein affected by protonation. The main objective of this work was to study the protonation-conformation coupling in CcOs and identify the molecular factors that control the protonation state of some key residues. In order to directly capture the interplay between protonation and conformational effects, we have performed constant-pH MD simulations of an A1-type CcO inserted into a lipid bilayer in two redox states (oxidized and reduced) at physiological pH. From the simulations, we were able to identify several groups with unusual titration behavior that are highly dependent on the protein redox state, including the A-propionate from heme a and the D-propionate from heme a3, two key groups possibly involved in proton pumping. The protonation state of these two groups is heavily influenced by subtle conformational changes in the protein (notably of R481(I) and R482(I)) and by small changes in the hydrogen bond network.

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Section: Constant-ph MD Simulationsmentioning

confidence: 99%

“…Simulations of two protein redox states were performed at pH 7, using our in-house stochastic titration method [29,33,[36][37][38][39]. Several CcO residues, such as the key heme propionate groups, sampled different protonation states during the simulations.…”

Section: Introductionmentioning

confidence: 99%

Coupling between protonation and conformation in cytochrome c oxidase: Insights from constant-pH MD simulations

Oliveira¹,

Campos²,

Baptista³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Bioenergetics

Self Cite

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“…Unlike the classical MD simulations where protonation states of all titratable groups are kept fixed, the constant pH MD simulations allow for the change of protonation states of titratable groups during the simulations. The sampling of protonation states in the protein is usually implemented using the PBE [64][65][66] or GB model [62] combined with Monte Carlo sampling. The constant pH MD simulations account for the aqueous environment in a realistic way and, therefore, their main contribution is likely to be in studies of pH-dependent conformational changes and the pH-dependence of protein stability [42].…”

Section: Macroscopic Models Turn Microscopicmentioning

confidence: 99%

Electrostatics in proteins and protein–ligand complexes

Kukić

Nielsen

2010

Future Medicinal Chemistry

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“…Often referred to as constant pH MD (CPHMD) simulations, the titration coordinate is typically implemented in either a discrete manner [31][32][33][34][35][36][37][38][39][40][41][42][43] where protonation states are modified with an MC step at some regular MD interval or using a continuous function [44][45][46] that describes the protonation state via the k dynamics method developed by Brooks and coworkers. [47][48][49] Recent studies have shown that CPHMD is a reliable and robust method that is capable of predicting pK a values in a variety of biomolecular systems.…”

Section: Introductionmentioning

confidence: 99%

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

2013

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: Tombusviruses, such as Carnation Italian ringspot virus (CIRV), encode a protein homodimer called p19 that is capable of suppressing RNA silencing in their infected hosts by binding to and sequestering short-interfering RNA (siRNA) away from the RNA silencing pathway. P19 binding stability has been shown to be sensitive to changes in pH but the specific amino acid residues involved have remained unclear. Using constant pH molecular dynamics simulations, we have identified key pH-dependent residues that affect CIRV p19-siRNA binding stability at various pH ranges based on calculated changes in the free energy contribution from each titratable residue. At high pH, the deprotonation of Lys60, Lys67, Lys71, and Cys134 has the largest effect on the binding stability. Similarly, deprotonation of several acidic residues (Asp9, Glu12, Asp20, Glu35, and/or Glu41) at low pH results in a decrease in binding stability. At neutral pH, residues Glu17 and His132 provide a small increase in the binding stability and we find that the optimal pH range for siRNA binding is between 7.0 and 10.0. Overall, our findings further inform recent experiments and are in excellent agreement with data on the pH-dependent binding profile.

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Constant-pH Molecular Dynamics with Ionic Strength Effects: Protonation−Conformation Coupling in Decalysine

Cited by 114 publications

References 60 publications

Coupling between protonation and conformation in cytochrome c oxidase: Insights from constant-pH MD simulations

Coupling between protonation and conformation in cytochrome c oxidase: Insights from constant-pH MD simulations

Electrostatics in proteins and protein–ligand complexes

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

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