Double proton coupled charge transfer in DNA.
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Base Pairing↗
Biomedical subjects
Michele Parrinello
Publications and source records attributed to Michele Parrinello.
Crystal structure transformations in SiO2 from classical and ab initio metadynamics.
Silica is the main component of the Earth's crust and is also of great relevance in many branches of materials science and technology. Its phase diagram is rather intricate and exhibits many different crystalline phases. The reported propensity to amorphization and the strong influence on the outcome of the initial structure and of the pressurization protocol indicate the presence of metastability and large kinetic barriers. As a consequence, theory is also faced with great difficulties and our understanding of the complex transformation mechanisms is still very sketchy despite a large number of simulations. Here, we introduce a substantial improvement of the metadynamics method, which finally brings simulations in close agreement with experiments. We unveil the subtle and non-intuitive stepwise mechanism of the pressure-induced transformation of fourfold-coordinated alpha-quartz into sixfold-coordinated stishovite at room temperature. We also predict that on compression fourfold-coordinated coesite will transform into the post-stishovite alpha-PbO2-type phase. The new method is far more efficient than previous methods, and for the first time the study of complex structural phase transitions with many intermediates is within the reach of molecular dynamics simulations. This insight will help in designing new experimental protocols capable of steering the system towards the desired transition.
Journal Article↗
Exploring the gating mechanism in the ClC chloride channel via metadynamics.
Computer simulations have been used to probe the gating mechanism in the Salmonella serovar typhimurium chloride channel (st-ClC). Specifically, the recently developed metadynamics methodology has been exploited to construct free energy surfaces as a function of the positions of either one or two chloride ions inside the pore, the position and protonation state of the key E148 residue, and the number of water molecules coordinating the translocating ions. The present calculations confirm the multi-ion mechanism in which an ion-push-ion effect lowers the main barriers to chloride ion translocation. When a second anion is taken into account, the barrier for chloride passage through the E148 narrow region is computed to be 6 kcal/mol in the wild-type channel, irrespective of the protonation state of the E148 residue, which is shown to only affect the entrance barrier. In the E148A mutant, this barrier is much lower, amounting to 3 kcal/mol. The metadynamics calculations reported herein also demonstrate that before reaching the periplasmic solution, chloride ions have to overcome an additional barrier arising from two different effects, namely the rearrangement of their solvation shell and a flip in the backbone angles of the residues E148 and G149, which reside at the end of the alphaF helix.
Chloride Channels↗
A QUICKSTEP-based quantum mechanics/molecular mechanics approach for silica.
Quantum mechanics/molecular mechanics (QM/MM) approaches are currently used to describe several properties of silica-based systems, which are local in nature and require a quantum description of only a small number of atoms around the site of interest, e.g., local chemical reactivity or spectroscopic properties of point defects. We present a QM/MM scheme for silica suitable to be implemented in the general QM/MM framework recently developed for large scale molecular dynamics simulations, within the QUICKSTEP approach to the description of the quantum region. Our scheme has been validated by computing the structural and dynamical properties of an oxygen vacancy in alpha-quartz, a prototypical defect in silica. We have found that good convergence in the Si-Si bond length and formation energy is achieved by using a quantum cluster of only eight atoms in size. We check the suitability of the method for molecular dynamics and evaluate the Si-Si bond frequency from the velocity-velocity correlation function.
Journal Article↗
Equilibrium free energies from nonequilibrium metadynamics.
In this Letter we propose a new formalism to map history-dependent metadynamics in a Markovian process. We apply this formalism to model Langevin dynamics and determine the equilibrium distribution of a collection of simulations. We demonstrate that the reconstructed free energy is an unbiased estimate of the underlying free energy and analytically derive an expression for the error. The present results can be applied to other history-dependent stochastic processes, such as Wang-Landau sampling.
Journal Article↗
Ab initio molecular dynamics study of heterogeneous oxidation of graphite by means of gas-phase nitric acid.
The interaction between gas-phase nitric acid and the graphite surface is taken as a simple model of interactions occurring at the surface of atmospheric soot particles. In particular, we study the heterogeneous processes that lead to the dissociation of the nitric acid and the production of nitrous acid. The atomistic details of the reaction mechanisms are reproduced by use of the new metadynamics method. The binding interactions of the HNO3 molecule and its fragments with the graphite surface are calculated, and the role of the surface in catalyzing the reaction is taken into account. From the reactive trajectory generated by the metadynamics, it is seen that the path goes through several different intermediate states. We analyze in detail the electronic structures and spin density distributions of the relevant products and report on the mechanisms and the main features of the transition regions relative to all the activated processes observed.
Journal Article↗
Efficient reconstruction of complex free energy landscapes by multiple walkers metadynamics.
Recently, we have introduced a new method, metadynamics, which is able to sample rarely occurring transitions and to reconstruct the free energy as a function of several variables with a controlled accuracy. This method has been successfully applied in many different fields, ranging from chemistry to biophysics and ligand docking and from material science to crystal structure prediction. We present an important development that speeds up metadynamics calculations by orders of magnitude and renders the algorithm much more robust. We use multiple interacting simulations, walkers, for exploring and reconstructing the same free energy surface. Each walker contributes to the history-dependent potential that, in metadynamics, is an estimate of the free energy. We show that the error on the reconstructed free energy does not depend on the number of walkers, leading to a fully linear scaling algorithm even on inexpensive loosely coupled clusters of PCs. In addition, we show that the accuracy and stability of the method are much improved by combining it with a weighted histogram analysis. We check the validity of our new method on a realistic application.
Algorithms↗
Metadynamics simulation of prion protein: beta-structure stability and the early stages of misfolding.
In the present study we have used molecular dynamics simulations to study the stability of the antiparallel beta-sheet in cellular mouse prion protein (PrP(C)) and in the D178N mutant. In particular, using the recently developed non-Markovian metadynamics method, we have evaluated the free energy as a function of a reaction coordinate related to the beta-sheet disruption/growth. We found that the antiparallel beta-sheet is significantly weaker in the pathogenic D178N mutant than in the wild-type PrP(C). The destabilization of PrP(C) beta-structure in the D178N mutant is correlated to the weakening of the hydrogen bonding network involving the mutated residue, Arg164 and Tyr128 side chains. This in turn indicates that such a network apparently provides a safety mechanism for the unzipping of the antiparallel beta-sheet in the PrP(C). We conclude that the antiparallel beta-sheet is likely to undergo disruption rather than growth under pathogenic conditions, in agreement with recent models of the misfolded monomer that assume a parallel beta-helix.
Animals↗
Lithium hydroxide phase transition under high pressure: an ab initio molecular dynamics study.
The high-pressure phase transition in the deuterated lithium hydroxide crystalline state has been studied by Car-Parrinello molecular dynamics simulations, in the constant-pressure, constant-temperature ensemble. The recently developed metadynamics approach has been applied to encourage the system to transform into different phases in an affordable simulation time. A previously not completely characterized high-pressure phase has been obtained. The structural and spectroscopic properties have been studied and compared with the neutron scattering, infrared and Raman measurements. It has been found that the calculated structure differs slightly from the experimental hypothesis, and that the presence of strong hydrogen bonds is the source of the red shift and of the characteristic features of the OD-stretching bands in both IR and Raman spectra.
Journal Article↗
Anisotropy of Earth's D'' layer and stacking faults in the MgSiO3 post-perovskite phase.
The post-perovskite phase of (Mg,Fe)SiO3 is believed to be the main mineral phase of the Earth's lowermost mantle (the D'' layer). Its properties explain numerous geophysical observations associated with this layer-for example, the D'' discontinuity, its topography and seismic anisotropy within the layer. Here we use a novel simulation technique, first-principles metadynamics, to identify a family of low-energy polytypic stacking-fault structures intermediate between the perovskite and post-perovskite phases. Metadynamics trajectories identify plane sliding involving the formation of stacking faults as the most favourable pathway for the phase transition, and as a likely mechanism for plastic deformation of perovskite and post-perovskite. In particular, the predicted slip planes are {010} for perovskite (consistent with experiment) and {110} for post-perovskite (in contrast to the previously expected {010} slip planes). Dominant slip planes define the lattice preferred orientation and elastic anisotropy of the texture. The {110} slip planes in post-perovskite require a much smaller degree of lattice preferred orientation to explain geophysical observations of shear-wave anisotropy in the D'' layer.
Journal Article↗
Nonperiodic boundary conditions for solvated systems.
The simulation of charged and/or strongly polar solutes represents a challenge for standard molecular-dynamics techniques. The use of periodic boundary conditions (PBCs) leads to artifacts due to the interaction between two replicas in the presence of the long-range Coulomb forces. A way to avoid these problems is the use of nonperiodic boundary conditions. A possible realization is to consider a finite system, a sphere, embedded in a reaction field described by the method of the images. In the present work the modified image approximation has been implemented in a molecular-dynamics code and optimized for the use of two standard solvents, water and acetonitrile. The methodology has then been applied to investigate the conformational changes in water-solvated alanine dipeptide. The free-energy surface calculated with this method is comparable to that obtained with PBC.
Acetonitriles↗
The role of the peripheral anionic site and cation-pi interactions in the ligand penetration of the human AChE gorge.
We 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.
Acetylcholinesterase↗
Exploring polymorphism: the case of benzene.
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Benzene↗
Charge localization in DNA fibers.
We study by first-principles molecular dynamics the mechanism of electron hole (positive charge) localization in a laboratory realizable radical cation Z DNA crystal. We find that at room temperature structural deformation does not provide an efficient localization mechanism. Instead, we find evidence for the importance of changes in the protonation state for stabilizing the radical defect.
DNA, Z-Form↗
Assessing the accuracy of metadynamics.
Metadynamics is a powerful technique that has been successfully exploited to explore the multidimensional free energy surface of complex polyatomic systems and predict transition mechanisms in very different fields, ranging from chemistry and solid-state physics to biophysics. We here derive an explicit expression for the accuracy of the methodology and provide a way to choose the parameters of the method in order to optimize its performance.
Journal Article↗
A recipe for the computation of the free energy barrier and the lowest free energy path of concerted reactions.
The recently introduced hills method (Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12562) is a powerful tool to compute the multidimensional free energy surface of intrinsically concerted reactions. We have extended this method by focusing our attention on localizing the lowest free energy path that connects the stable reactant and product states. This path represents the most probable reaction mechanism, similar to the zero temperature intrinsic reaction coordinate, but also includes finite temperature effects. The transformation of the multidimensional problem to a one-dimensional reaction coordinate allows for accurate convergence of the free energy profile along the lowest free energy path using standard free energy methods. Here we apply the hills method, our lowest free energy path search algorithm, and umbrella sampling to the prototype S(N)2 reaction. The hills method replaces the in many cases difficult problem of finding a good reaction coordinate with choosing relatively simple collective variables, such as the bond lengths of the broken and formed chemical bonds. The second part of the paper presents a guide to using the hills method, in which we test and fine-tune the method for optimal accuracy and efficiency using the umbrella sampling results as a reference.
Journal Article↗
Topological defects and bulk melting of hexagonal ice.
We use classical molecular dynamics combined with the recently developed metadynamics method [Laio, A.; Parrinello, M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 20] to study the process of bulk melting in hexagonal ice. Our simulations show that bulk melting is mediated by the formation of topological defects which preserve the coordination of the tetrahedral network. Such defects cluster to form a defective region involving about 50 molecules with a surprisingly long lifetime. The subsequent formation of coordination defects triggers the transition to the liquid state.
Ice↗
Flexible docking in solution using metadynamics.
We 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: beta-trypsin/benzamidine, beta-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.
Benzamidines↗