1,721,023 research outputs found
RNA Unwinding from Reweighted Pulling Simulations
No full textThe forming and melting of complementary base pairs in RNA duplexes are conformational transitions required to accomplish a plethora of biological functions. Yet the dynamic steps of these transitions have not been quantitatively characterized at the molecular level. In this work, the base opening process was first enforced by atomistic pulling simulations and then analyzed with a novel reweighting scheme, which allowed the free-energy profile along any suitable reaction coordinate, for example, solvation, to be reconstructed. The systematic application of such approach to different base-pair combinations provides a molecular motion picture of helix opening, which is validated by comparison with an extensive set of experimental observations and links them to the enzyme-dependent unwinding mechanism. The RNA intrinsic dynamics disclosed in this work could rationalize the directionality observed in RNA-processing molecular machineries
Ligand-induced stabilization of the aptamer terminal helix in the add adenine riboswitch
Full text linkRiboswitches are structured mRNA elements that modulate gene expression. They undergo conformational changes triggered by highly specific interactions with sensed metabolites. Among the structural rearrangements engaged by riboswitches, the forming and melting of the aptamer terminal helix, the so called P1 stem, is essential for genetic control. The structural mechanisms by which this conformational change is modulated upon ligand binding mostly remain to be elucidated. Here, we used pulling molecular dynamics simulations to study the thermodynamics of the P1 stem in the add adenine riboswitch. The P1 ligand-dependent stabilization was quantified in terms of free energy and compared with thermodynamic data. This comparison suggests a model for the aptamer folding in which direct P1-ligand interactions play a minor role on the conformational switch when compared with those related to the ligand-induced aptamer preorganization
Symmetry and asymmetry in the unwinding of nucleic acids
No full textThe forming and melting of complementary base pairs in RNA and DNA duplexes are conformational transitions re- quired to accomplish a plethora of biological functions. Using fully atomistic simulation we have shown that RNA unwind- ing occurs by a stepwise process in which the probability of unbinding of the base on the 5’ strand is significantly higher than that on the 3’ strand [Colizzi and Bussi JACS, 2012]. The asymmetry in the RNA unwinding dynamics is compli- ant with the mechanism of helicase activity shown by proto- typical DEx(H/D) RNA helicases and could allow decipher- ing the basis of the evolutionary pressure responsible for the unwinding mechanism catalyzed by RNA-duplex processing enzymes. In this spirit and from a broader standpoint, here we use a topology-based coarse-grain model to compare and characterize the mechanism of unwinding for both DNA and RNA. The (a)symmetric behavior of the 3’- and 5’-strand could be related to the (bi)directionality observed in molecular machineries processing nucleic acids
Induced fit modeling nella beta-idrossiacil-ACP deidratasi (FabZ) di Plasmodium falciparum
No full textSingle-molecule pulling simulations can discern active from inactive enzyme inhibitors
No full textUnderstanding ligand-protein recognition and interaction processes is of primary importance for structure-based drug design. Traditionally, several approaches combining docking and molecular dynamics (MD) simulations have been exploited to investigate the physicochemical properties of complexes of pharmaceutical interest. Even if the geometric properties of a modeled protein-ligand complex can be well predicted by computational methods, it is challenging to rank a series of analogues in a consistent fashion with biological data. In the unique beta-hydroxyacyl-ACP dehydratase of Plasmodium falciparum (PfFabZ), the application of standard molecular docking and MD simulations was partially sufficient to shed light on the activity of previously discovered inhibitors. Complementing docking results with atomistic simulations in the steered molecular dynamics (SMD) framework, we devised an in silico approach to study molecular interactions and to compare the binding characteristics of ligand analogues. We hypothesized an interaction model that both explained the biological activity of known ligands, and provided insight into designing novel enzyme inhibitors. Mimicking single-molecule pulling experiments, we used SMD-derived force profiles to discern active from inactive compounds for the first time. A new compound was designed and its biological activity toward the PfFabZ enzyme predicted. Finally, the computational predictions were experimentally confirmed, highlighting the robustness of the drug design approach presented herein
Circulating intercellular adhesion molecule 1 as a marker of disease progression in cutaneous melanoma
No full text
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
- …
