title: Time-averaged distributions of solute and solvent motions: exploring proton wires of GFP and PfM2DH.
abstract: Proton translocation pathways of selected variants of the green fluorescent protein (GFP) and Pseudomonas fluorescens mannitol 2-dehydrogenase (PfM2DH) were investigated via an explicit solvent molecular dynamics-based analysis protocol that allows for direct quantitative relationship between a crystal structure and its time-averaged solute-solvent structure obtained from simulation. Our study of GFP is in good agreement with previous research suggesting that the proton released from the chromophore upon photoexcitation can diffuse through an extended internal hydrogen bonding network that allows for the proton to exit to bulk or be recaptured by the anionic chromophore. Conversely for PfM2DH, we identified the most probable ionization states of key residues along the proton escape channel from the catalytic site to bulk solvent, wherein the solute and high-density solvent crystal structures of binary and ternary complexes were properly reproduced. Furthermore, we proposed a plausible mechanism for this proton translocation process that is consistent with the state-dependent structural shifts observed in our analysis. The time-averaged structures generated from our analyses facilitate validation of MD simulation results and provide a comprehensive profile of the dynamic all-occupancy solvation network within and around a flexible solute, from which detailed hydrogen-bonding networks can be inferred. In this way, potential drawbacks arising from the elucidation of these networks by examination of static crystal structures or via alternate rigid-protein solvation analysis procedures can be overcome. Complementary studies aimed at the effective use of our methodology for alternate implementations (e.g., ligand design) are currently underway.
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Camilo
authors.initials: C
authors.lastname: Velez-Vega
authors.forename: Daniel J J
authors.initials: DJ
authors.lastname: McKay
authors.forename: Vibhas
authors.initials: V
authors.lastname: Aravamuthan
authors.forename: Robert
authors.initials: R
authors.lastname: Pearlstein
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D049452:Green Fluorescent Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008354:Mannitol Dehydrogenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009068:Movement; D009154:Mutation; D017433:Protein Structure, Secondary; D011522:Protons; D011551:Pseudomonas fluorescens / Q000201:enzymology; D012997:Solvents / Q000737:chemistry*; D013997:Time Factors
chemical_list: D011522:Protons; D012997:Solvents; D049452:Green Fluorescent Proteins; D008354:Mannitol Dehydrogenases