42 research outputs found
Coarse-grained simulations of RNA and DNA duplexes
Although RNAs play many cellular functions little is known about the dynamics
and thermodynamics of these molecules. In principle, all-atom molecular
dynamics simulations can investigate these issues, but with current computer
facilities, these simulations have been limited to small RNAs and to short
times.
HiRe-RNA, a recently proposed high-resolution coarse-grained for RNA that
captures many geometric details such as base pairing and stacking, is able to
fold RNA molecules to near-native structures in a short computational time. So
far it had been applied to simple hairpins, and here we present its application
to duplexes of a couple dozen nucleotides and show how with our model and with
Replica Exchange Molecular Dynamics (REMD) we can easily predict the correct
double helix from a completely random configuration and study the dissociation
curve. To show the versatility of our model, we present an application to a
double stranded DNA molecule as well.
A reconstruction algorithm allows us to obtain full atom structures from the
coarse-grained model. Through atomistic Molecular Dynamics (MD) we can compare
the dynamics starting from a representative structure of a low temperature
replica or from the experimental structure, and show how the two are
statistically identical, highlighting the validity of a coarse-grained approach
for structured RNAs and DNAs.Comment: 28 pages, 11 figure
Ab initio RNA folding
RNA molecules are essential cellular machines performing a wide variety of
functions for which a specific three-dimensional structure is required. Over
the last several years, experimental determination of RNA structures through
X-ray crystallography and NMR seems to have reached a plateau in the number of
structures resolved each year, but as more and more RNA sequences are being
discovered, need for structure prediction tools to complement experimental data
is strong. Theoretical approaches to RNA folding have been developed since the
late nineties when the first algorithms for secondary structure prediction
appeared. Over the last 10 years a number of prediction methods for 3D
structures have been developed, first based on bioinformatics and data-mining,
and more recently based on a coarse-grained physical representation of the
systems. In this review we are going to present the challenges of RNA structure
prediction and the main ideas behind bioinformatic approaches and physics-based
approaches. We will focus on the description of the more recent physics-based
phenomenological models and on how they are built to include the specificity of
the interactions of RNA bases, whose role is critical in folding. Through
examples from different models, we will point out the strengths of
physics-based approaches, which are able not only to predict equilibrium
structures, but also to investigate dynamical and thermodynamical behavior, and
the open challenges to include more key interactions ruling RNA folding.Comment: 28 pages, 18 figure
Structural transitions in the RNA 7SK 5' hairpin and their effect on HEXIM binding.
7SK RNA, as part of the 7SK ribonucleoprotein complex, is crucial to the regulation of transcription by RNA-polymerase II, via its interaction with the positive transcription elongation factor P-TEFb. The interaction is induced by binding of the protein HEXIM to the 5' hairpin (HP1) of 7SK RNA. Four distinct structural models have been obtained experimentally for HP1. Here, we employ computational methods to investigate the relative stability of these structures, transitions between them, and the effects of mutations on the observed structural ensembles. We further analyse the results with respect to mutational binding assays, and hypothesize a mechanism for HEXIM binding. Our results indicate that the dominant structure in the wild type exhibits a triplet involving the unpaired nucleotide U40 and the base pair A43-U66 in the GAUC/GAUC repeat. This conformation leads to an open major groove with enough potential binding sites for peptide recognition. Sequence mutations of the RNA change the relative stability of the different structural ensembles. Binding affinity is consequently lost if these changes alter the dominant structure
10 simple rules to create a serious game, illustrated with examples from structural biology
Serious scientific games are games whose purpose is not only fun. In the
field of science, the serious goals include crucial activities for scientists:
outreach, teaching and research. The number of serious games is increasing
rapidly, in particular citizen science games, games that allow people to
produce and/or analyze scientific data. Interestingly, it is possible to build
a set of rules providing a guideline to create or improve serious games. We
present arguments gathered from our own experience ( Phylo , DocMolecules ,
HiRE-RNA contest and Pangu) as well as examples from the growing literature on
scientific serious games
Soluble endoglin reduces thrombus formation and platelet aggregation via interaction with αIIbβ3 integrin
14 p.-6 fig.Background: The circulating form of human endoglin (sEng) is a cleavage product of membrane-bound endoglin present on endothelial cells. Because sEng encompasses an RGD motif involved in integrin binding, we hypothesized that sEng would be able to bind integrin αIIbβ3, thereby compromising platelet binding to fibrinogen and thrombus stability.Methods: In vitro human platelet aggregation, thrombus retraction, and secretion-competition assays were performed in the presence of sEng. Surface plasmon resonance (SPR) binding and computational (docking) analyses were carried out to evaluate protein-protein interactions. A transgenic mouse overexpressing human sEng (hsEng+) was used to measure bleeding/rebleeding, prothrombin time (PT), blood stream, and embolus formation after FeCl3-induced injury of the carotid artery.Results: Under flow conditions, supplementation of human whole blood with sEng led to a smaller thrombus size. sEng inhibited platelet aggregation and thrombus retraction, interfering with fibrinogen binding, but did not affect platelet activation. SPR binding studies demonstrated that the specific interaction between αIIbβ3 and sEng and molecular modeling showed a good fitting between αIIbβ3 and sEng structures involving the endoglin RGD motif, suggesting the possible formation of a highly stable αIIbβ3/sEng. hsEng+ mice showed increased bleeding time and number of rebleedings compared to wild-type mice. No differences in PT were denoted between genotypes. After FeCl3 injury, the number of released emboli in hsEng+ mice was higher and the occlusion was slower compared to controls.Conclusions: Our results demonstrate that sEng interferes with thrombus formation and stabilization, likely via its binding to platelet αIIbβ3, suggesting its involvement in primary hemostasis control.Promex Stiftung für die Forschung Foundation
Consejo Superior de Investigaciones Científicas; Grant/Award Number: 201920E022
Spanish Ministry of Science, Innovation & Universities; Grant/Award Number: RTI2018-102242-B-I00
Comunidad de Madrid; Grant/Award Number: S2022/BMD-7278Peer reviewe
Modeling RNA structures and folding
A dissertation submitted in partial fulfillment of the requirements for the HABILITATIONàHABILITATIONà DIRIGER des RECHERCHES UFR Sciences du Vivant, Université Paris Diderot-Paris
The Coarse-Grained OPEP Force Field for Non-Amyloid and Amyloid Proteins
International audienceno abstrac