O to bR transition in bacteriorhodopsin occurs through a proton hole mechanism

2021 ◽  
Vol 118 (39) ◽  
pp. e2024803118
Author(s):  
Denis Maag ◽  
Thilo Mast ◽  
Marcus Elstner ◽  
Qiang Cui ◽  
Tomáš Kubař
Keyword(s):  
Free Energy ◽  
Structural Features ◽  
Chloride Ions ◽  
Proton Exchange ◽  
Coupling Mechanism ◽  
Free Energy Surface ◽  
Water Network ◽  
Hydration Level ◽  
Energy Simulations ◽  
Dynamics Simulations

Extensive classical and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations are used to establish the structural features of the O state in bacteriorhodopsin (bR) and its conversion back to the bR ground state. The computed free energy surface is consistent with available experimental data for the kinetics and thermodynamics of the O to bR transition. The simulation results highlight the importance of the proton release group (PRG, consisting of Glu194/204) and the conserved arginine 82 in modulating the hydration level of the protein cavity. In particular, in the O state, deprotonation of the PRG and downward rotation of Arg82 lead to elevated hydration level and a continuous water network that connects the PRG to the protonated Asp85. Proton exchange through this water network is shown by ∼0.1-μs semiempirical QM/MM free energy simulations to occur through the generation and propagation of a proton hole, which is relayed by Asp212 and stabilized by Arg82. This mechanism provides an explanation for the observation that the D85S mutant of bacteriorhodopsin pumps chloride ions. The electrostatics–hydration coupling mechanism and the involvement of all titration states of water are likely applicable to many biomolecules involved in bioenergetic transduction.

scholarly journals Cavity hydration dynamics in cytochrome c oxidase and functional implications

2017 ◽  
Vol 114 (42) ◽  
pp. E8830-E8836 ◽  
Author(s):  
Chang Yun Son ◽  
Arun Yethiraj ◽  
Qiang Cui
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Proton Transfer ◽  
Molecular Dynamics Simulations ◽  
Transmembrane Protein ◽  
Wetting Transition ◽  
Protonation State ◽  
Hydration Level ◽  
Level Change ◽  
Dynamics Simulations

Cytochrome c oxidase (CcO) is a transmembrane protein that uses the free energy of O2 reduction to generate the proton concentration gradient across the membrane. The regulation of competitive proton transfer pathways has been established to be essential to the vectorial transport efficiency of CcO, yet the underlying mechanism at the molecular level remains lacking. Recent studies have highlighted the potential importance of hydration-level change in an internal cavity that connects the proton entrance channel, the site of O2 reduction, and the putative proton exit route. In this work, we use atomistic molecular dynamics simulations to investigate the energetics and timescales associated with the volume fluctuation and hydration-level change in this central cavity. Extensive unrestrained molecular dynamics simulations (accumulatively ∼4 μs) and free energy computations for different chemical states of CcO support a model in which the volume and hydration level of the cavity are regulated by the protonation state of a propionate group of heme a3 and, to a lesser degree, the redox state of heme a and protonation state of Glu286. Markov-state model analysis of ∼2-μs trajectories suggests that hydration-level change occurs on the timescale of 100–200 ns before the proton-loading site is protonated. The computed energetic and kinetic features for the cavity wetting transition suggest that reversible hydration-level change of the cavity can indeed be a key factor that regulates the branching of proton transfer events and therefore contributes to the vectorial efficiency of proton transport.

Displacement of carbonates in Ca2UO2(CO3)3 by amidoxime-based ligands from free-energy simulations

2018 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Bo Li ◽  
Chad Priest ◽  
De-en Jiang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Umbrella Sampling ◽  
Nacl Solution ◽  
Classical Molecular Dynamics ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Free Energy Profiles

Classical molecular dynamics simulations coupled with umbrella sampling reveal the atomistic processes and free-energy profiles of the displacement of carbonate groups in the Ca2UO2(CO3)3 complex by amidoxime-based ligands in a 0.5 M NaCl solution.

scholarly journals pKa Calculations of Asp26 in Thioredoxin with Alchemical Free Energy Simulations and Hirshfeld-I Atomic Charges

2018 ◽  
Author(s):  
Aharon Gomez Llanos ◽  
Esteban Vöhringer-Martinez
Keyword(s):  
Free Energy ◽  
Proton Transfer ◽  
Force Field ◽  
Gibbs Free Energy ◽  
Atomic Charges ◽  
Energy Cycle ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Aspartate Residue ◽  
Experimental Reference

Thioredoxin is a protein that has been used as model system by various computational methods to predict the pK<sub>a</sub> of aspartate residue Asp26 which is 3.5 units higher than the solvent exposed Asp20. Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation the Gibbs free energy of proton transfer between the two aspartic acid residues is calculated with the Amber99sb force field in alchemical transformation. The varying polarization of Asp20/26 in different molecular environments and protonation states is described by Hirshfeld-I (HI) atomic charges obtained from the averaged polarized electron density. Our results show that the Gibbs free energy of proton transfer is dependent on the protein conformation, the proper sampling of the neighbouring Lys57 positions and on water molecules entering the hydrophobic cavity upon deprotonating Asp26. The inclusion of polarization of both aspartate residues in the free energy cycle by the HI atomic charges improve the results from the nonpolarizable force field and reproduces the experimental reference delta pK<sub>a</sub> value.

scholarly journals Molecular dynamics simulations of liquid silica crystallization

2018 ◽  
Vol 115 (21) ◽  
pp. 5348-5352 ◽  
Author(s):  
Haiyang Niu ◽  
Pablo M. Piaggi ◽  
Michele Invernizzi ◽  
Michele Parrinello
Keyword(s):  
Free Energy ◽  
Nucleation Theory ◽  
Classical Nucleation Theory ◽  
Free Energy Surface ◽  
X Ray Diffraction ◽  
Collective Variables ◽  
Atomic Simulations ◽  
The Difference ◽  
Dynamics Simulations ◽  
Good Agreement

Silica is one of the most abundant minerals on Earth and is widely used in many fields. Investigating the crystallization of liquid silica by atomic simulations is of great importance to understand the crystallization mechanism; however, the high crystallization barrier and the tendency of silica to form glasses make such simulations very challenging. Here we have studied liquid silica crystallization to β-cristobalite with metadynamics, using X-ray diffraction (XRD) peak intensities as collective variables. The frequent transitions between solid and liquid of the biased runs demonstrate the highly successful use of the XRD peak intensities as collective variables, which leads to the convergence of the free-energy surface. By calculating the difference in free energy, we have estimated the melting temperature of β-cristobalite, which is in good agreement with the literature. The nucleation mechanism during the crystallization of liquid silica can be described by classical nucleation theory.

scholarly journals Combining free energy simulations and NMR chemical-shift perturbation to identify transient cation-π contacts in proteins

2019 ◽  
Author(s):  
André A. O. Reis ◽  
Raphael S. R. Sayegh ◽  
Sandro R. Marana ◽  
Guilherme M. Arantes
Keyword(s):  
Free Energy ◽  
Chemical Shift ◽  
Catalytic Domain ◽  
Chemical Shifts ◽  
Umbrella Sampling ◽  
Terminal Segment ◽  
Functional Roles ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations

AbstractFlexible protein regions containing cationic and aromatic side-chains exposed to solvent may form transient cation-π interactions with structural and functional roles. To evaluate their stability and identify important intramolecular cation-π contacts, a combination of free energy profiles estimated from umbrella sampling with molecular dynamics simulations and chemical shift perturbations (CSP) obtained from NMR experiments is applied here to the complete catalytic domain of human phosphatase Cdc25B. This protein is a good model system for transient cation-π interactions as it contains only one Trp residue (W550) in the disordered C-terminal segment and a total of 17 Arg residues, many exposed to solvent. Eight putative Arg-Trp pairs were simulated here. Only R482 and R544 show bound profiles corresponding to important transient cation-π interactions, while the others have dissociative or almost flat profiles. These results are corroborated by CSP analysis of three Cdc25B point mutants (W550A, R482A and R544A) disrupting cation-π contacts. The proposed validation of statistically representative molecular simulations by NMR spectroscopy could be applied to identify transient contacts of proteins in general but carefully, as NMR chemical shifts are sensitive to changes in both molecular contacts and conformational distributions.

Temperature- and Pressure-Induced Unfolding of a Mutant of Staphylococcal Nuclease A

1996 ◽  
Author(s):  
Maurice R. Eftink ◽  
Glen D. Ramsay
Keyword(s):  
Free Energy ◽  
Thermodynamic Stability ◽  
Structural Features ◽  
Staphylococcal Nuclease ◽  
Tryptophan Residue ◽  
Hybrid Protein ◽  
Wild Type ◽  
Free Energy Surface ◽  
Native State ◽  
Maximum Stability

Nuclease conA is a hybrid version of Staphylococcal nuclease that contains a six amino acid (β-turn substitute from concanavalin A. This hybrid protein has a much lower thermodynamic stability than does the wild-type protein. This enables the unfolding of the protein to be achieved easily by several types of perturbations. From temperature-, pressure-, and denaturant-induced unfolding studies, we have found the free energy change for unfolding, ΔG°un, to be approximately 1.4 kcal mo−1 at pH 7, 0.1 M NaCI, and 20 °C, as compared to a thermodynamic stability of approximately 5.5–6 kcal mo−1 for wild-type nuclease A. Due to its reduced thermodynamic stability, nuclease conA also shows evidence of unfolding at low-temperature (cold denaturation), with a temperature of maximum stability of 13–15 °C. The thermal unfolding of nuclease conA is shown to be two-state by simultaneous measurement of fluorescence and CD changes as a function of temperature, using a modified AVIV CD instrument. Increased hydrostatic pressure unfolds nuclease conA in what appears to be a two-state manner, with an apparent of ΔV°un approximately —100 ml mol−1. From studies of the pressure (p)-induced unfolding of this hybrid protein as a function of temperature (T), we can define the complete p-T free energy surface for the unfolding transition. In auxiliary studies, we have characterized the fluorescence intensity decay and anisotropy decay of the single tryptophan residue (Trp-140) of nuclease conA in the native state and in the unfolded state induced by temperature, pressure, and denaturant. For each type of perturbation, there is a red shift in fluorescence, a lowering of the mean fluorescence lifetime, and a lowering of the rotational correlation time of the tryptophan residue to a value of ~1 ns (compared to 10–15 ns for the native state). The thermodynamics of the unfolding of proteins has received renewed interest in recent years, owing to the availability of a rich variety of mutant proteins and to advances in our understanding of their structural features. Among the questions being asked are, What are the relative energetic contributions of the hydrophobic effect and other interaction forces?

scholarly journals Exploring the effectiveness of SARS-CoV-2 3CLpro inhibitors through molecular dynamics and binding free energy simulations

2020 ◽  
Author(s):  
ANDREY PINHEIRO ◽  
GABRIEL XAVIER ◽  
ANDREI SIQUEIRA ◽  
ALEX LIMA ◽  
DÉLIA AGUIAR ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Vaccine Development ◽  
Virus Disease ◽  
Binding Free Energy ◽  
Zinc Database ◽  
Energy Simulations ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
The Impact

Abstract In December 2019, in the city of Wuhan in China, a novel Coronavirus was identified as the causative agent of a Severe Acute Respiratory Syndrome, later called Corona Virus Disease 2019 (COVID-19). Since the identification of the agent and sequencing of its genome, proteases such as 3CLpro and PLprothat participate in the viral cycle have been identified as possible pharmacological targets. This study aimed to evaluate the affinity of SARS-CoV-2 3CLpro (PDB 6LU7) concerning promising binders identified by other studies using virtual screening against the ZINC database and other molecules within the possibility of inhibiting the protease, such as Hydroxychloroquine, Chloroquine, and Remdesivir. Around 1,140 ns of molecular dynamics simulations were performed to evaluate stability and binding free energy values of protein-ligand complexes (60 ns for each ligand). The estimated affinity, based on 5000 frames trajectories, revealed that N3, 11b, remdesivir and a ZINC database ligand are the most promising inhibitors of 3CLpro.Given that most studies present energy results based on docking runs and one-frame coordinates analyses, the results found may present a more accurate energy value and may help experimental approaches to developing a drug against COVID-19. Despite the importance of vaccine development, alternative strategies, such as specific viral inhibitors, are important to reduce the impact of the disease on people.

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

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