130 research outputs found
Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science
No full textMetadynamics is a powerful algorithm that can be used both for reconstructing the free energy
and for accelerating rare events in systems described by complex Hamiltonians, at the classical
or at the quantum level. In the algorithm the normal evolution of the system is biased by a
history-dependent potential constructed as a sum of Gaussians centered along the trajectory
followed by a suitably chosen set of collective variables. The sum of Gaussians is exploited for
reconstructing iteratively an estimator of the free energy and forcing the system to escape from
local minima. This review is intended to provide a comprehensive description of the
algorithm, with a focus on the practical aspects that need to be addressed when one attempts to
apply metadynamics to a new system: (i) the choice of the appropriate set of collective
variables; (ii) the optimal choice of the metadynamics parameters and (iii) how to control the
error and ensure convergence of the algorithm
Investigating drug-target association and dissociation mechanisms using metadynamics-based algorithms.
No full textThis Account highlights recent advances and discusses major challenges in the field of drug-target recognition, binding, and unbinding studied using metadynamics-based approaches, with particular emphasis on their role in structure-based design. Computational chemistry has significantly contributed to drug design and optimization in an extremely broad range of areas, including prediction of target druggability and drug likeness, de novo design, fragment screening, ligand docking, estimation of binding affinity, and modulation of ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. Computationally driven drug discovery must continuously adapt to keep pace with the evolving knowledge of the factors that modulate the pharmacological action of drugs. There is thus an urgent need for novel computational approaches that integrate the vast amount of complex information currently available for small (bio)organic compounds, biologically relevant targets and their complexes, while also accounting accurately for the thermodynamics and kinetics of drug-target association, the intrinsic dynamical behavior of biomolecular systems, and the complexity of protein-protein networks. Understanding the mechanism of drug binding to and unbinding from biological targets is fundamental for optimizing lead compounds and designing novel biologically active ones. One major challenge is the accurate description of the conformational complexity prior to and upon formation of drug-target complexes. Recently, enhanced sampling methods, including metadynamics and related approaches, have been successfully applied to investigate complex mechanisms of drugs binding to flexible targets. Metadynamics is a family of enhanced sampling techniques aimed at enhancing the rare events and reconstructing the underlying free energy landscape as a function of a set of order parameters, usually referred to as collective variables. Studies of drug binding mechanisms have predicted the most probable association and dissociation pathways and the related binding free energy profile. In addition, the availability of an efficient open-source implementation, running on cost-effective GPU (i.e., graphical processor unit) architectures, has considerably decreased the learning curve and the computational costs of the methods, and increased their adoption by the community. Here, we review the recent contributions of metadynamics and other enhanced sampling methods to the field of drug-target recognition and binding. We discuss how metadynamics has been used to search for transition states, to predict binding and unbinding paths, to treat conformational flexibility, and to compute free energy profiles. We highlight the importance of such predictions in drug discovery. Major challenges in the field and possible solutions will finally be discussed
Efficient reconstruction of complex free energy landscapes by multiple walkers metadynamics
No full textRecently, 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
I mss. Gervasio : schede umanistiche
No full textTra i mss. del Gervasio e il corposo carteggio si ritrovano non pochi riferimenti agli autori napoletani gravitanti attorno all'Accademia Pontaniana: Ga- briele Altilio, Girolamo Britonio, Elisio Calenzio, il Cariteo, Angelo Colocci, Antonio Epicuro, Giovan Berardino Fuscano, Francesco Galeota, Notturno Na- poletano, Giovanni Pontano, Jacopo Sannazaro, Luigi Tansillo, e tanti altri, che, con lo storico Pietro Summonte, costituiscono le personalità di rilievo della cul- tura partenopea della prima metà del Cinquecento, che il Gervasio tentò di porre in luce attraverso la redazione di schede biobibliografiche dei singoli autori. In quelle schede ci sono ancora utili riferimenti a mss. o a opere andate ormai disperse, che attendono giovani studiosi della letteratura partenopea del Cinquecento. Ma anche dei secoli successivi.The Gervasio manuscripts and the relevant weighty correspondence contain numerous references to Neapolitan authors gravitating around the Accademia Pontaniana and that especially in the first half of the Sixteenth century made a significant contribution to poetry writing in Naples. Gabriele Altilio, Girolamo Britonio, Elisio Calenzio, Cariteo, Angelo Colocci, Antonio Epicuro, Giovan Berardino Fuscano, Francesco Galeota, Notturno Napoletano, Giovanni Pontano, Jacopo Sannazaro, Luigi Tansillo and many others who, alongside the historian Pietro Summonte, constitute the major figures of Neapolitan culture in the first half of the Sixteenth century which Gervasio attempted to describe via bio-bibliographical dossiers for each author. These dossiers also offer useful information concerning lost manuscripts or works, awaiting young scholars of Sixteenth-century Neapolitan literature. But also of the succeeding centuries
Cyclin-dependent kinases: bridging their structure and function through computations
No full textCyclin-dependent kinases (CDKs) are one of the most promising target families for drug discovery for several
diseases, such as cancer and neurodegenerative disorders. Over the years, structural insights on CDKs have
demonstrated high protein plasticity, with several cases where two or more structures of the same protein adopt
different conformations. This has generated a great deal of interest in understanding the relationship between CDK
structure and function. Here, we highlight how computer simulations have recently contributed in characterizing
some key rare and transient events in CDKs, such as the reaction transition state and activation loop movement.
Although not yet fully defined, we can now portray the enzymatic mechanism and plasticity of CDKs at high spatial
and temporal resolution. These theoretical studies bridge with experiments and highlight structural determinants
that could help in designing specific CDK inhibitors
Assessing the accuracy of metadynamics
No full textMetadynamics 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
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
Evaluación de la capacidad antioxidante de vinos con los métodos ORAC-PGR y ORAC-FL
No full textEstudios demuestran que el consumo moderado de vino es beneficioso para la salud en la prevención de enfermedades crónicas asociadas al estrés oxidativo. Los antioxidantes son importantes para el organismo por la capacidad que tienen de proteger las macromoléculas biológicas contra el daño oxidativo. El vino tinto posee polifenoles de reconocida capacidad antioxidante.
La capacidad antioxidante del vino está relacionada con el contenido de polifenoles y su concentración cambia según su variedad, área de producción, técnicas agrarias, proceso de vinificación, vendimia, clima. Por esto, en la presente tesis se consideraron varias cepas , de diversas regiones del país para establecer una comparación.
La cercanía entre las altas cumbres andinas y el Pacífico dan origen a una topografía determinante en el cultivo de la vid. Estas características generan un sinnúmero de microclimas, cada uno de los cuales ofrece condiciones distintas que le dan a las uvas
características propias e inimitables con alta calidad.
Las zonas vinícolas más conocidas de Chile se ubican en el Valle Central que se extiende de Norte a Sur entre los ríos Maipo y Maule y que limita al Este con la cordillera de Los Andes y al Oeste con el Océano Pacífico.
Las muestras de vino fueron seleccionadas de acuerdo a varias regiones del país, del Norte la marca Santa Emiliana del valle de Limarí o Valle del Elqui, de la zona central Misiones de Rengo Ventisquero Clásico, Sunrise y Doña Dominga justo en el centro de Chile, entre el pie andino y la cordillera de la costa, se encuentran los valles de Cachapoal y Colchagua que juntos dan vida a Rapel: una de las zonas vitivinícolas más famosas del país.
Respecto a los vinos del sur de Chile se escogió la marca Canepa del Valle del Maule Corresponde a la parte más austral del Valle Central y la que tiene la mayor extensión de viñedos de todo Chile.
El Valle del Maule, posee un gran potencial para producir vinos de alta calidad gracias a la calidad de sus suelos, el clima y la abundancia de agua. La interacción entre el clima y el suelo ejerce un efecto directo sobre la madurez de los taninos y el balance entre el alcohol y la acidez, dando como resultado vinos concentrados, maduros y frescos, y que además auguran un gran potencial de guarda.
Esta tesis tiene como objetivo evaluar la capacidad antioxidante de diversas marcas de vinos tintos chilenos. Para ello se estudia el contenido total de polifenoles de ocho vinos de la cepa Cabernet Souvignon de diferentes años y zonas del país.
Para determinar el contenido de fenoles se utiliza el método Folin-Ciocalteau La capacidad antioxidante es estudiada por la metodologia ORAC usando Fluoresceina y Pirogalol rojo como moléculas blanco a fin de comparar la eficiencia de ambos métodos.
Los resultados indican que el índice Folín de lo vinos más altos corresponde a los vinos Canepa, Casillero del Diablo, Misiones de Rengo, Cousiño Macul y Ventisquero clásico.
Tales vinos presentan la mayor cantidad de polifenoles y una mayor calidad de sus flavonoides.
Al evaluar la capacidad antioxidante por el método ORAC-PGR y ORAC-FL los valores
de ORAC-FL fueron dos veces mayores que los valores ORAC- que confirma la relación
ORAC PGR/ ORAC FL que se han obtenido en trabajos realizados con estas técnicas en
vinos chilenos.
Existe una correlación entre los valores de ORAC y los índices Folín y se aprecia una
correlación entre ORAC-FL y ORAC-PGR.
El índice ORAC de las muestras de vino fue diferente, dependiendo de la molécula blanco
utilizado. Esto demuestra que el método ORAC es muy dependiente de las condiciones
empleadas
Investigation of biologically relevant proteins using the combination of magnetic tweezers experiments and a novel molecular dynamics method
No full textWe have developed a novel metric for the path collective variables. This metric measures the distance from reference configurations using a combination of simple collective variables, with their contributions optimised for maximising the path entropy. We have called this approach COMet-Path (computational optimisation of a metric for path collective variables). We have validated it using transitions between the conformational minima of trialanine peptide. To compare it to earlier RMSD metric, we have also applied it to the computation of the absolute binding free energy for the Dasatinib binding to c-Src kinase, and we have obtained good agreement with our previous results. We have then applied this approach also to the problem of predicting absolute binding free energies. As a test system, we used a set of epoxide hydrolase inhibitors. We have developed a technique that allows us to predict their binding free energy values with high accuracy at low computational cost. It has also allowed us to understand more about which collective variables and optimisation settings offer better results for difficult problems. In the next part, we investigated the WW domain of PQBP1, where a Y65C single point mutation is responsible for the emergence of the Golabi-Ito-Hall syndrome. Through the use of magnetic tweezers, we showed that the mutant exhibits unexpected behaviour and sensitivity to redox conditions, unlike the wild type. We have also attempted to model the behaviour of these domains using several molecular dynamics approaches, including COMet-Path. Finally, we applied magnetic tweezers also to the problem of the binding of talin to integrin. We have been able to determine the geometry of this interaction and were able to quantify the force required to break it, along with the unfolding force of the individual components of the talin head domain
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