0000000000068022
AUTHOR
Giovanni Ciccotti
Multiphoton Absorption of Myoglobin Nitric-Oxide complex: Relaxation by D-NEMD of a Stationary State
ABSTRACT: The photodissociation and geminate recombination of nitric oxide in myoglobin, under continuous illumination, is modeled computationally. The relaxation of the photon energy into the protein matrix is also considered in a single simulation scheme that mimics a complete experimental setup. The dynamic approach to non-equilibrium molecular dynamics is used, starting from a steady state, to compute its relaxation to equilibrium. Simulations are conducted for the native form of sperm whale myoglobin and for two other mutants, V68W and L29F, illustrating a fair diversity of spatial and temporal geminate recombination processes. Energy flow to the heme and immediate protein environment …
Mapping CO diffusion paths in Myoglobin with the Single Sweep Method
The pathways of diffusion and escape of a CO molecule inside and out a myoglobin protein are investigated. Specifically, the three-dimensional potential of mean force (PMF or free energy) of the CO molecule position inside the protein is calculated by using the single-sweep method in concert with fully resolved atomistic simulations in explicit solvent.The results are interpreted under the assumption that the diffusion of the ligand can be modeled as a navigation on the PMF in which the ligand hops between the PMF local minima following the minimum free energy paths (MFEPs) with rates set by the free energy barriers that need to be crossed. We calculate all these quantities --local minima, …
Flux expressions and NEMD perturbations for models of semi-flexible molecules
We derive energy and momentum flux expressions, for systems composed of a general class of semi-flexible molecules, in the Ciccotti-Ferrario-Ryckaert linear constraint formalism. According to this formalism, the whole set of Cartesian coordinates is divided into basic (independent) and secondary (dependent) subsets. It is found that energy and momentum flux vectors have a simple and general expression using both basic and secondary coordinates. In the case of non-equilibrium molecular dynamics, we give general and simple heat and shear flow algorithms, deriving the dissipative fluxes in the space of all Cartesian coordinates. In comparison with previous derivations for some models of flexib…
Mapping the network of pathways of CO diffusion in myoglobin.
The pathways of diffusion of a CO molecule inside a myoglobin protein and toward the solvent are investigated. Specifically, the three-dimensional potential of mean force (PMF or free energy) of the CO molecule position inside the protein is calculated by using the single-sweep method in concert with fully resolved atomistic simulations in explicit solvent. The results are interpreted under the assumption that the diffusion of the ligand can be modeled as a navigation on the PMF in which the ligand hops between the PMF local minima following the minimum free energy paths (MFEPs) with rates set by the free energy barriers that need to be crossed. Here, all the local minima of the PMF, the MF…
Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniques, we study the ligand-induced conformational changes of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) simulations we investigate the AChBP transition between the apo and the agonist-bound state. In long standard MD simulations, both confo…
A Structural Model of the Human α7 Nicotinic Receptor in an Open Conformation
International audience; Nicotinic acetylcholine receptors (nAchRs) are ligand-gated ion channels that regulate chemical transmission at the neuromuscular junction. Structural information is available at low resolution from open and closed forms of an eukaryotic receptor, and at high resolution from other members of the same structural family, two prokaryotic orthologs and an eukary- otic GluCl channel. Structures of human channels however are still lacking. Homology modeling and Molecular Dynamics simulations are valuable tools to predict structures of unknown proteins, however, for the case of human nAchRs, they have been unsuccessful in providing a stable open structure so far. This is du…
Structural and Dynamic Properties of the Homodimeric Hemoglobin from Scapharca inaequivalvis Thr-72→Ile Mutant: Molecular Dynamics Simulation, Low Temperature Visible Absorption Spectroscopy, and Resonance Raman Spectroscopy Studies
AbstractMolecular dynamics simulations, low temperature visible absorption spectroscopy, and resonance Raman spectroscopy have been performed on a mutant of the Scapharca inaequivalvis homodimeric hemoglobin, where residue threonine 72, at the subunit interface, has been substituted by isoleucine. Molecular dynamics simulation indicates that in the Thr-72→Ile mutant several residues that have been shown to play a role in ligand binding fluctuate around orientations and distances similar to those observed in the x-ray structure of the CO derivative of the native hemoglobin, although the overall structure remains in the T state. Visible absorption spectroscopy data indicate that in the deoxy …
Molecular dynamics simulation of carboxy-myoglobin embedded in a trehalose-water matrix
AbstractWe report on a molecular dynamics (MD) simulation of carboxy-myoglobin (MbCO) embedded in a water-trehalose system. The mean square fluctuations of protein atoms, calculated at different temperatures in the 100–300K range, are compared with those from a previous MD simulation on an H2O-solvated MbCO and with experimental data from Mössbauer spectroscopy and incoherent elastic neutron scattering on trehalose-coated MbCO. The results show that, for almost all the atomic classes, the amplitude of the nonharmonic motions stemming from the interconversion among the protein’s conformational substates is reduced with respect to the H2O-solvated system, and their onset is shifted toward hig…
Molecular dynamics simulation of sucrose- and trehalose-coated carboxy-myoglobin
We performed a room temperature molecular dynamics (MD) simulation on a system containing 1 carboxy-myoglobin (MbCO) molecule in a sucrose–water matrix of identical composition (89% [sucrose/(sucrose + water)] w/w) as for a previous trehalose–water–MbCO simulation (Cottone et al., Biophys J 2001;80:931–938). Results show that, as for trehalose, the amplitude of protein atomic mean-square fluctuations, on the nanosecond timescale, is reduced with respect to aqueous solutions also in sucrose. A detailed comparison as a function of residue number evidences mobility differences along the protein backbone, which can be related to a different efficacy in bioprotection. Different heme pocket struc…
Atomic Mean-Square Displacements in Proteins by Molecular Dynamics: A Case for Analysis of Variance
AbstractInformation on protein internal motions is usually obtained through the analysis of atomic mean-square displacements, which are a measure of variability of the atomic positions distribution functions. We report a statistical approach to analyze molecular dynamics data on these displacements that is based on probability distribution functions. Using a technique inspired by the analysis of variance, we compute unbiased, reliable mean-square displacements of the atoms and analyze them statistically. We applied this procedure to characterize protein thermostability by comparing the results for a thermophilic enzyme and a mesophilic homolog. In agreement with previous experimental observ…