207 research outputs found
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
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
A refined pH-dependent coarse-grained model for peptide structure prediction in aqueous solution
Introduction: Peptides carry out diverse biological functions and the knowledge of the conformational ensemble of polypeptides in various experimental conditions is important for biological applications. All fast dedicated softwares perform well in aqueous solution at neutral pH.Methods: In this study, we go one step beyond by combining the Debye-Hückel formalism for charged-charged amino acid interactions and a coarse-grained potential of the amino acids to treat pH and salt variations.Results: Using the PEP-FOLD framework, we show that our approach performs as well as the machine-leaning AlphaFold2 and TrRosetta methods for 15 well-structured sequences, but shows significant improvement in structure prediction of six poly-charged amino acids and two sequences that have no homologous in the Protein Data Bank, expanding the range of possibilities for the understanding of peptide biological roles and the design of candidate therapeutic peptides
A Multiscale Approach to Characterize the Early Aggregation Steps of the Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35
The self-organization of peptides into amyloidogenic oligomers is one of the key events for a wide range of molecular and degenerative diseases. Atomic-resolution characterization of the mechanisms responsible for the aggregation process and the resulting structures is thus a necessary step to improve our understanding of the determinants of these pathologies. To address this issue, we combine the accelerated sampling properties of replica exchange molecular dynamics simulations based on the OPEP coarse-grained potential with the atomic resolution description of interactions provided by all-atom MD simulations, and investigate the oligomerization process of the GNNQQNY for three system sizes: 3-mers, 12-mers and 20-mers. Results for our integrated simulations show a rich variety of structural arrangements for aggregates of all sizes. Elongated fibril-like structures can form transiently in the 20-mer case, but they are not stable and easily interconvert in more globular and disordered forms. Our extensive characterization of the intermediate structures and their physico-chemical determinants points to a high degree of polymorphism for the GNNQQNY sequence that can be reflected at the macroscopic scale. Detailed mechanisms and structures that underlie amyloid aggregation are also provided
A multiscale approach to characterize the early aggregation steps of the amyloid-forming peptide GNNQQNY from the yeast prion sup-35
ABSTRACT: The self-organization of peptides into amyloidogenic oligomers is one of the key events for a wide range of molecular and degenerative diseases. Atomic-resolution characterization of the mechanisms responsible for the aggregation process and the resulting structures is thus a necessary step to improve our understanding of the determinants of these pathologies. To address this issue, we combine the accelerated sampling properties of replica exchange molecular dynamics simulations based on the OPEP coarse-grained potential with the atomic resolution description of interactions provided by all-atom MD simulations, and investigate the oligomerization process of the GNNQQNY for three system sizes: 3-mers, 12-mers and 20-mers. Results for our integrated simulations show a rich variety of structural arrangements for aggregates of all sizes. Elongated fibril-like structures can form transiently in the 20-mer case, but they are not stable and easily interconvert in more globular and disordered forms. Our extensive characterization of the intermediate structures and their physico-chemical determinants points to a high degree of polymorphism for the GNNQQNY sequence that can be reflected at the macroscopic scale. Detailed mechanisms and structures that underlie amyloid aggregation are also provided
Cutoff scores for the “Interest game”, an application for the assessment of diminished interest in neurocognitive disorders
Diminished interest is a core feature of apathy that shows high prevalence in people with Mild and Major Neurocognitive disorders (NCD). In the clinical setting, apathy is mainly assessed using clinical scales and questionnaires, but new technologies are starting to be employed to complement classical instruments. Here, we explored the performance of the “Interest game,” a ludic application that assesses personal interests, in discriminating between persons with and without diminished interest based on the Apathy Diagnostic Criteria. Two hundred and twenty-seven elderly participants (56 healthy controls, 118 persons with mild-NCD, and 53 with major-NCD) completed the Interest game and were assessed by clinicians concerning the presence and the severity of apathy. Results showed that the application scores varied with the presence of apathy, the type of disorder, and the education level. Cutoff scores calculated for persons with Mild-NCD resulted in a sensitivity of 0.68 and a specificity of 0.65 for the main score index, suggesting the interest of employing this application in the clinical setting to complement the classical assessment
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