1,721,004 research outputs found
Similarities and Differences in Ligand Binding to Protein and RNA Targets: The Case of Riboflavin
No full textIt is nowadays clear that RNA molecules can play active roles in several biological processes. As a result, an increasing number of RNAs are gradually being identified as potentially druggable targets. In particular, noncoding RNAs can adopt highly organized conformations that are suitable for drug binding. However, RNAs are still considered challenging targets due to their complex structural dynamics and high charge density. Thus, elucidating relevant features of drug-RNA binding is fundamental for advancing drug discovery. Here, by using Molecular Dynamics simulations, we compare key features of ligand binding to proteins with those observed in RNA. Specifically, we explore similarities and differences in terms of (i) conformational flexibility of the target, (ii) electrostatic contribution to binding free energy, and (iii) water and ligand dynamics. As a test case, we examine binding of the same ligand, namely riboflavin, to protein and RNA targets, specifically the riboflavin (RF) kinase and flavin mononucleotide (FMN) riboswitch. The FMN riboswitch exhibited enhanced fluctuations and explored a wider conformational space, compared to the protein target, underscoring the importance of RNA flexibility in ligand binding. Conversely, a similar electrostatic contribution to the binding free energy of riboflavin was found. Finally, greater stability of water molecules was observed in the FMN riboswitch compared to the RF kinase, possibly due to the different shape and polarity of the pockets
Implicit solvent methods for free energy estimation
No full textSolvation is a fundamental contribution in many biological processes and especially in molecular binding. Its estimation can be performed by means of several computational approaches. The aim of this review is to give an overview of existing theories and methods to estimate solvent effects giving a specific focus on the category of implicit solvent models and their use in Molecular Dynamics. In many of these models, the solvent is considered as a continuum homogenous medium, while the solute can be represented at the atomic detail and at different levels of theory. Despite their degree of approximation, implicit methods are still widely employed due to their trade-off between accuracy and efficiency. Their derivation is rooted in the statistical mechanics and integral equations disciplines, some of the related details being provided here. Finally, methods that combine implicit solvent models and molecular dynamics simulation, are briefly described
Charged dielectric spheres interacting in electrolytic solution: A linearized Poisson–Boltzmann equation model
No full textWe present an analytical theory of electrostatic interactions of two spherical dielectric particles of arbitrary radii and dielectric constants, immersed into a polarizable ionic solvent (assuming that the linearized Poisson-Boltzmann framework holds) and bearing arbitrary charge distributions expanded in multipolar terms. The presented development entails a novel two-center re-expansion analytical theory that expands upon and improves the existing ones, bypassing the conventional expansions in modified Bessel functions. On this basis, we develop a specific matrix formalism that facilitates the construction of asymptotic expansions in ascending order of Debye screening terms of potential coefficients, which are then employed to find exact closed-form expressions for the total electrostatic energy. In particular, this work allows us to explicitly and precisely quantify the k-screened terms of the potential coefficients and mutual interaction energy. Specific cases of monopolar and dipolar distributions are described in particular detail. Comprehensive numerical examples and tests of series convergence and the relative balance of leading and higher-order terms of the mutual interaction energy are presented depending on the inter-particle distance and particles' radii. The results of this work find application in soft matter modeling and, in particular, in computational biophysics and colloid science, where the availability of increasingly larger experimental structures at the atomic-level resolution makes numerical treatment challenging and calls for more efficient expressions and an increased range of validity
BiKi Life Sciences:A New Suite for Molecular Dynamics and Related Methods in Drug Discovery
Full text linkIn this paper, we introduce the BiKi Life Sciences suite. This software makes it easy for computational medicinal chemists to run ad hoc molecular dynamics protocols in a novel and task-oriented environment; as a notebook, BiKi (acronym of Binding Kinetics) keeps memory of any activity together with dependencies among them. It offers unique accelerated protein-ligand binding/unbinding methods and other useful tools to gain actionable knowledge from molecular dynamics simulations and to simplify the drug discovery process.</p
Kinetics of protein-ligand unbinding via smoothed potential molecular dynamics simulations
No full textDrug discovery is expensive and high-risk. Its main reasons of failure are lack of efficacy and toxicity of a drug candidate. Binding affinity for the biological target has been usually considered one of the most relevant figures of merit to judge a drug candidate along with bioavailability, selectivity and metabolic properties, which could depend on off-target interactions. Nevertheless, affinity does not always satisfactorily correlate with in vivo drug efficacy. It is indeed becoming increasingly evident that the time a drug spends in contact with its target (aka residence time) can be a more reliable figure of merit. Experimental kinetic measurements are operatively limited by the cost and the time needed to synthesize compounds to be tested, to express and purify the target, and to setup the assays. We present here a simple and efficient molecular-dynamics-based computational approach to prioritize compounds according to their residence time. We devised a multiple-replica scaled molecular dynamics protocol with suitably defined harmonic restraints to accelerate the unbinding events while preserving the native fold. Ligands are ranked according to the mean observed scaled unbinding time. The approach, trivially parallel and easily implementable, was validated against experimental information available on biological systems of pharmacological relevance
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Force Field Parametrization of Metal Ions From Statistical Learning Techniques
No full textA novel statistical procedure has been developed to optimize the parameters of non-bonded force fields of metal ions in soft matter. The criterion for the optimization is the minimization of the deviations from ab initio forces and energies calculated for model systems. The method exploits the combination of the linear ridge regression and the cross-validation techniques with the di˙erential evolution algorithm. Wide freedom in the choice of the functional form of the force fields is allowed since both linear and non-linear parameters can be optimized. In order to maximize the information content of the data employed in the fitting procedure, the composition of the training set is entrusted to a combinatorial optimization algorithm which maximizes the dissimilarity of the included instances. The methodology has been validated using the force field parametrization of five metal ions (Zn2+, Ni2+, Mg2+, Ca2+, and Na+) in water as test cases
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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