Proton Transfer at Metal Sites in Proteins Studied by Quantum Mechanical Free-Energy Perturbations

2008 ◽  
Vol 4 (6) ◽  
pp. 985-1001 ◽  
Author(s):  
Markus Kaukonen ◽  
Pär Söderhjelm ◽  
Jimmy Heimdal ◽  
Ulf Ryde
Keyword(s):  
Free Energy ◽  
Proton Transfer ◽  
Quantum Mechanical ◽  
Free Energy Perturbations

scholarly journals Quantum Mechanical/Molecular Mechanical Analysis of the Catalytic Mechanism of Phosphoserine Phosphatase

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3342 ◽  
Author(s):  
Dieter Krachtus ◽  
Jeremy Smith ◽  
Petra Imhof
Keyword(s):  
Free Energy ◽  
Proton Transfer ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Free Energy Calculations ◽  
Reaction Coordinate ◽  
Reaction Pathways ◽  
Quantum Mechanical ◽  
Energy Calculation ◽  
Phosphoserine Phosphatase

Phosphoserine phosphatase (PSP), a member of the haloacid dehalogenase (HAD) superfamily that comprises the vast majority of phosphotransferases, is likely a steady-state regulator of the level of d-serine in the brain. The proposed catalytic cycle of PSP consists of a two-step mechanism: formation of a phospho-enzyme intermediate by phosphate transfer to Asp11 and its subsequent hydrolysis. Our combined quantum mechanical/molecular mechanical (QM/MM) calculations of the reaction pathways favour a dissociative mechanism of nucleophilic substitution via a trigonal-planar metaphosphate-like configuration for both steps, associated with proton transfer to the leaving group or from the nucleophile. This proton transfer is facilitated by active site residue Asp13 that acts as both a general base and a general acid. Free energy calculation on the reaction pathways further support the structural role of the enzymatic environment and the active site architecture. The choice of a proper reaction coordinate along which to bias the free energy calculations can be guided by a projection of the canonical reaction coordinate obtained from a chain-of-state optimisation onto important internal coordinates.

Long-range proton relay shows an inverse linear free energy relationship depending on the pKa of the hydrogen-bonded wire

RSC Advances ◽  
2015 ◽  
Vol 5 (4) ◽  
pp. 2669-2676 ◽  
Author(s):  
Binh Khanh Mai ◽  
Yongho Kim
Keyword(s):  
Free Energy ◽  
Proton Transfer ◽  
Long Range ◽  
Quantum Mechanical ◽  
Linear Free Energy Relationship ◽  
Quantum Mechanical Calculations ◽  
Linear Free Energy ◽  
Proton Relay ◽  
Hydrogen Bonded

The long-range proton transfer dependence on the pKa of hydroxyl molecules in hydrogen (H)-bonded wires was investigated using quantum mechanical calculations.

A molecular dynamics study on liquid 1-octanol. Part 3. Evaluating octanol/water partition coefficients of novel thrombin inhibitors via free-energy perturbations

2005 ◽  
Vol 102 (5) ◽  
pp. 542-553 ◽  
Author(s):  
César Augusto Fernandes De Oliveira ◽  
Cristiano Ruch Werneck Guimarães ◽  
Heloisa De Mello ◽  
Aurea Echevarria ◽  
Ricardo Bicca De Alencastro
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Partition Coefficients ◽  
Thrombin Inhibitors ◽  
Free Energy Perturbations

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.

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