1,721,029 research outputs found
SAMPL6 blind predictions of water-octanol partition coefficients using nonequilibrium alchemical approaches
No full textIn this paper, we compute, by means of a non equilibrium alchemical technique, the water-octanol partition coefficients (LogP) for a series of drug-like compounds in the context of the SAMPL6 challenge initiative. Our blind predictions are based on three of the most popular non-polarizable force fields, CGenFF, GAFF2, and OPLS-AA and are critically compared to other MD-based predictions produced using free energy perturbation or thermodynamic integration approaches with stratification. The proposed non-equilibrium method emerges has a reliable tool for LogP prediction, systematically being among the top performing submissions in all force field classes for at least two among the various indicators such as the Pearson or the Kendall correlation coefficients or the mean unsigned error. Contrarily to the widespread equilibrium approaches, that yielded apparently very disparate results in the SAMPL6 challenge, all our independent prediction sets, irrespective of the adopted force field and of the adopted estimate (unidirectional or bidirectional) are, mutually, from moderately to strongly correlated
SAMPL9 blind predictions for toluene/water partition coefficients using nonequilibrium alchemical approaches
Full text linkWe present our blind prediction of the toluene-water partition coefficients in the context of the SAMPL9 challenge. For the calculation of the solvation free energies in water, toluene, and 1-octanol, we used an efficient MD-based nonequilibrium alchemical technique relying on the GAFF2 non-polarizable force field. The method is based on the fast-growth of an initially decoupled solute. Canonical sampling of the associated end-state is efficiently obtained by performing a Hamiltonian replica exchange simulation of the gas-phase solute molecule alone, combined with equilibrium configurations of the solvent. Before submitting the prediction, a pre-assessment of the method and of the force field was made by comparing with the known experimental counterpart the calculated octanol-water partition coefficients using different set of atomic charges. The analysis allowed to optimize our blind prediction for the toluene-water partition coefficients, providing at the same time valid clues for improving the performance and reliability of the non-polarizable force field in free energy calculations of drug-receptor systems
A General Algorithm for Computing Voronoi Volumes - Application to the Hydrated Crystal of Myoglobin
No full textIn this study is presented a general algorithm for computing Voronoi volumes of atoms or group of atoms in condensed phases. The method is essentially an extension of the Medvedev procedure to allow vertice determination for any Voronoi polyhedron, primitive or with degenerate vertices. The algorithm has been employed for computing time-averaged volumes in the hydrated crystal of met-myoglobin, using the data of a molecular dynamics simulation. The results, compared to previous volume determination in myoglobin, emphasize the fundamental role of solvent structure close to the protein surface in relation to the packing density properties of the residues. Relative volumes fluctuations of myoglobin residues have been found to be correlated to the corresponding mean square displacements from X-ray diffraction studies and to the theoretical hydration energies
SAMPL9 blind predictions using nonequilibrium alchemical approaches
Full text linkWe present our blind predictions for the Statistical Assessment of the
Modeling of Proteins and Ligands (SAMPL), 9th challenge, focusing on binding of
WP6 (carboxy-pillar[6]arene) with ammonium/diammonium cationic guests.
Host-guest binding free energies have been calculated using the recently
developed virtual double system single box approach, based on the enhanced
sampling of the bound and unbound end-states followed by fast switching
nonequilibrium alchemical simulations [M Macchiagodena, M Pagliai, M
Karrenbrock, G Guarnieri, F
Iannone, Procacci, J Chem Theory Comput, 16, 7260, 2020]. As far as Pearson
and Kendall coefficients are concerned, performances were acceptable and, in
general, better than those we submitted for calixarenes, cucurbituril-like open
cavitand, and beta-cyclodextrines in previous SAMPL host-guest challenges,
confirming the reliability of nonequilibrium approaches for absolute binding
free energy calculations. In comparison with previous submissions, we found,
nonetheless, a rather large mean signed error that we attribute to the way the
finite charge correction was addressed through the assumption of a neutralizing
background plasma.Comment: 23 pages, 6 figure and supporting material in a separate SI.pdf fil
Interaction of hydroxychloroquine with SARS-CoV2 functional proteins using all-atoms non-equilibrium alchemical simulations
No full textUsing a combination of enhanced sampling molecular dynamics techniques and non-equilibrium alchemical transformations with full atomistic details, we have shown that hydroxychloroquine (HCQ) may act as a mild inhibitor of important functional proteins for SARS-CoV2 replication, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19. This journal i
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
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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