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Alessandro Laio

Publications and source records attributed to Alessandro Laio.

At least 19 recordsLinked to original sources
PubMed2006

Dissociation mechanism of acetic acid in water.

The reaction mechanism for acetic acid dissociation in aqueous solution has been investigated by combining the metadynamics method with transition path sampling (TPS). By using collective variables that describe not only the deprotonation of the acid but also the solvation state of the hydronium ion and its distance from the acetate, a reactive trajectory in which stable separated ions were produced was obtained. More transition trajectories were sampled by using the TPS technique, taking the metadynamics trajectory as the initial trajectory. Two different dissociation reaction pathways were determined, one driven by the breaking of an H-bond formed by the water molecule in contact with the hydroxyl and involving the formation of a metastable contact ion pair and the other characterized by a direct transfer of the proton to the solution through an unstable Zundel-ion-like intermediate.

Acetic Acid↗
PubMed2006

Stability and structure of oligomers of the Alzheimer peptide Abeta16-22: from the dimer to the 32-mer.

Several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are associated with amyloid fibrils formed by different polypeptides. We probe the structure and stability of oligomers of different sizes of the fragment Abeta(16-22) of the Alzheimer beta-amyloid peptide using atomic-detail molecular dynamics simulations with explicit solvent. We find that only large oligomers form a stable beta-sheet aggregate, the minimum nucleus size being of the order of 8-16 peptides. This effect is attributed to better hydrophobic contacts and a better shielding of backbone-backbone hydrogen bonds from the solvent in bigger assemblies. Moreover, the observed stability of beta-sheet aggregates with a different number of layers can be explained on the basis of their solvent-accessible surface area. Depending on the stacking interface between the sheets, we observe straight or twisted structures, which could be linked to the experimentally observed polymorphism of amyloid fibrils. To compare our 32-mer structure to experimental data, we calculate its x-ray diffraction pattern. Good agreement is found between experimentally and theoretically determined reflections, suggesting that our model indeed closely resembles the structures found in vitro.

Amyloid beta-Peptides↗
PubMed2006

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↗
PubMed2006

A comparative theoretical study of dipeptide solvation in water.

Molecular dynamics studies have been performed on the zwitterionic form of the dipeptide glycine-alanine in water, with focus on the solvation and electrostatic properties using a range of theoretical methods, from purely classical force fields, through mixed quantum mechanical/molecular mechanical simulations, to fully quantum mechanical Car-Parrinello calculations. The results of these studies show that the solvation pattern is similar for all methods used for most atoms in the dipeptide, but can differ substantially for some groups; namely the carboxy and aminoterminii, and the backbone amid NH group. This might have implications in other theoretical studies of peptides and proteins with charged -NH(3) (+) and -CO(2) (-) side chains solvated in water. Hybrid quantum mechanical/molecular mechanical simulations successfully reproduce the solvation patterns from the fully quantum mechanical simulations (PACS numbers: 87.14.Ee, 87.15.Aa, 87.15.He, 71.15.Pd).

Alanine↗
PubMed2006

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↗
PubMed2006

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↗
PubMed2006

Are structural biases at protein termini a signature of vectorial folding?

Experimental investigations of the biosynthesis of a number of proteins have pointed out that part of the native structure may be acquired already during translation. We carried out a comprehensive statistical analysis of some average structural properties of proteins that have been put forward as possible signatures of this progressive buildup process. Contrary to a widespread belief, we found that there is no major propensity of the amino acids to form contacts with residues that are closer to the N-terminus. Moreover, we found that the C-terminus is significantly more compact and locally organized than the N-terminus. This bias, though, is unlikely to be related to vectorial effects, since it correlates with subtle differences in the primary sequence. These findings indicate that even if proteins acquire their structure vectorially, no signature of this seems to be detectable in their average structural properties.

Databases, Protein↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2005

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↗
PubMed2004

A molecular spring for vision.

Light absorption by the visual pigment rhodopsin leads to vision via a complex signal transduction pathway that is initiated by the ultrafast and highly efficient photoreaction of its chromophore, the retinal protonated Schiff base (RPSB). Here, we investigate this reaction in real time by means of unrestrained molecular dynamics simulations of the protein in a membrane mimetic environment, treating the chromophore at the density functional theory level. We demonstrate that a highly strained all-trans RPSB is formed starting from the 11-cis configuration (dark state) within approximately 100 fs by a minor rearrangement of the nuclei under preservation of the saltbridge with Glu113 and virtually no deformation of the binding pocket. Hence, the initial step of vision can be understood as the compression of a molecular spring by a minor change of the nuclear coordinates. This spring can then release its strain by altering the protein environment.

Algorithms↗
PubMed2004

Azulene-to-naphthalene rearrangement: the Car-Parrinello metadynamics method explores various reaction mechanisms.

We studied the thermal intramolecular and radical rearrangement of azulene to naphthalene by employing a novel metadynamics method based on Car-Parrinello molecular dynamics. We demonstrate that relatively short simulations can provide us with several possible reaction mechanisms for the rearrangement. We show that different choices of the collective coordinates can steer the reaction along different pathways, thus offering the possibility of choosing the most probable mechanism. We consider herein three intramolecular mechanisms and two radical pathways. We found the norcaradiene pathway to be the preferable intramolecular mechanism, whereas the spiran mechanism is the favored radical route. We obtained high activation energies for all the intramolecular pathways (81.5-98.6 kcal mol(-1)), whereas the radical routes have activation energies of 24-39 kcal mol(-1). The calculations have also resulted in elementary steps and intermediates not yet considered. A few attractive features of the metadynamics method in studying chemical reactions are pointed out.

Journal Article↗
PubMed2004

Influence of DNA structure on the reactivity of the guanine radical cation.

Oxidative damage of DNA via radical cation formation is a common cause of mutagenesis, cancer and of the physiological changes associated with aging. By using state-of-the-art ab initio molecular dynamics simulations, we study the mechanism that guides the first steps of this process. In the mechanism proposed here, guanine, which among the bases has the lowest oxidation potential, and the phosphate backbone play a crucial role. We found that the rate limiting step is the water protolysis. We illuminate the role of the local environment in considerably lowering the barrier. Of particular relevance in this respect is the role of the phosphate backbone.

Cytosine↗
PubMed2004

Correlations among hydrogen bonds in liquid water.

By performing computer simulations of water with the TIP5P potential we show that structures formed by two or more hydrogen bonds affect the dynamical and static properties of water, especially in the vicinity of freezing temperature. In particular, the short time correlation between two coupled hydrogen bonds cannot be predicted assuming the statistical independence of the single hydrogen bonds. This introduces an additional relaxation time of approximately 9 ps close to the freezing point. We also find that the time persistence of structures formed by several hydrogen bonds (the first solvation shell) correlates with the local density, which is smaller around water molecules with a long-living environment.

Computer Simulation↗
PubMed2004

A minimum free energy reaction path for the E2 reaction between fluoro ethane and a fluoride ion.

The 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.

Journal Article↗