1,720,985 research outputs found
Exploring complex protein-ligand recognition mechanisms with coarse metadynamics
No full textThe metadynamics method has been shown to be a valuable tool to study the mechanism of molecular recognition in atomistic detail [Gervasio, F. L.; et al. J. Am. Chem. Soc. 2005, 127, 2600]. However, it requires an a priori knowledge of all slow degrees of freedom relevant to the docking/undocking mechanism. Here we investigate a combination of docking/clustering with metadynamics performed with a subset of the necessary degrees of freedom (coarse metadynamics), and show that it provides a full mechanistic insight on the protein-ligand docking mechanism. Moreover, the proposed protocol is able to clearly distinguish between crystallographic and noncrystallographic poses of protein-ligand complexes, and also to find the transition state of the full undocking mechanism, thus giving an indication on the binding free energy
Flexible docking in solution using metadynamics
No full textWe apply our recently developed metadynamics method to the docking of ligands on flexible receptors in water solution. This method mimics the real dynamics of a ligand exiting or entering an enzyme
and in so doing reconstructs the free energy surface. We apply it to four docking cases: -trypsin/benzamidine, -trypsin/chlorobenzamidine, immunoglobulin McPC-603/phosphocholine, and cyclin-dependent kinase 2/staurosporine. In every case studied, the method is able to predict the docked geometry and the free energy of docking. Its added value with respect to many other available methods is that it
reconstructs the complete free energy surface, including all the relevant minima and the barriers between them
Free-Energy Landscape for β Hairpin Folding from Combined Parallel Tempering and Metadynamics
No full textWe develope a new free-energy method, based on the combination of parallel tempering and metadynamics, and apply this method to the calculation of the free-energy landscape of the folding β hairpin in explicit water. We show that the combined method greatly improves the performance of both parallel tempering and metadynamics. In particular, we are able to sample the high free-energy regions, which are not accessible with conventional parallel tempering. We use our results to calculate the difference in entropy and enthalpy between the folded and the unfolded state and to characterize the most populated configurations in the relevant free-energy basins
Influence of outer-shell metal ligands on the structural and electronic properties of horse liver alcohol dehydrogenase zinc active site
No full textAn analysis of the high resolution 3D structures of zinc enzymes shows that the Zn-His-carboxyl(ate)-HX (X = OH or NH) H-bond motif is common. We investigate here the influence of this motif in the active site of horse liver alcohol dehydrogenase, which features the Zn-His-Asp-H2O motif. Density functional theory calculations are carried out on models of the active site complexed with the NAD+ cofactor, in which the metal ion binds either the alcohol substrate [Bahnson et al. Proc. Nad. Acad. Sci. U. S.A 1997, 94, 1279712802](1) or a water molecule [Meijers et al. J. Biol. Chem. 2001, 276, 9316-9321].(2) Our calculations suggest that in both complexes the presence of Asp49 significantly affects the structural and electronic properties of the metal site. Furthermore, they show that inclusion of the Asp bound water molecule is required to describe the energetics correctly. Finally, they suggest that the Asp49/water pattern could play a role in the enzymatic reaction
Investigating biological systems with first principles Car-Parrinello molecular dynamics simulations
No full textDensity functional theory (DFT)-based Car–Parrinello molecular dynamics (CPMD) simulations describe the time evolution of molecular systems without resorting to a predefined potential energy surface. CPMD and hybrid molecular mechanics/CPMD schemes have recently enabled the calculation of redox properties of electron transfer proteins in their complex biological environment. They provided structural and spectroscopic information on novel platinum-based anticancer drugs that target DNA, also setting the basis for the construction of force fields for the metal lesion. Molecular mechanics/CPMD also lead to mechanistic hypotheses for a variety of metalloenzymes. Recent advances that increase the accuracy of DFT and the efficiency of investigating rare events are further expanding the domain of CPMD applications to biomolecules
A minimum free energy reaction path for the E2 reaction between fluoro ethane and a fluoride ion
No full textThe prototype binuclear elimination (E2) reaction illustrates the mechanism of a large number of biochemical and industrial applied processes but has received surprisingly little attention in theoretical studies compared to, for example, the substitution (SN2) reaction. This is due to its concerted mechanism, which requires an independent description of the three bonds that are being formed or broken. In this work, we have taken the advantage of a new and promising methodology to efficiently sample intrinsically multidimensional free-energy surfaces. We locate the lowest free-energy reaction path in the 3D configurational space and use this finite-temperature intrinsic reaction coordinate in an umbrella sampling scheme to access the temperature contributions to high accuracy. The small increase of the barrier and the decrease of the overall endothermicity for the E2 reaction due to entropic contributions is non-trivial. Moreover, our strategy to efficiently handle multiple reaction coordinates could be a great benefit to many chemistry-related fields, such as enzyme catalysis, reactions in solution, and nucleation processes
The role of the peripheral anionic site and cation-pi interactions in the ligand penetration of the human AChE gorge.
No full textWe study the ligand (tetramethylammonium) recognition by the peripheral anionic site and its penetration of the human AChE gorge by using atomistic molecular dynamics simulations and our recently developed metadynamics method. The role of both the peripheral anionic site and the formation of cation-pi interactions in the ligand entrance are clearly shown. In particular, a simulation with the W286A mutant shows the fundamental role of this residue in anchoring the ligand at the peripheral anionic site of the enzyme and in positioning it prior to the gorge entrance. Once the ligand is properly oriented, the formation of specific and synchronized cation-pi interactions with W86, F295, and Y341 enables the gorge penetration. Eventually, the ligand is stabilized in a free energy basin by means of cation-pi interactions with W86
Essential dynamics and metadynamics studies of the conformational changes in the activation loop and PSSARLE of Cdk5
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