Biology subjects

Contessoto, V.

Publications and source records attributed to Contessoto, V..

4 recordsLinked to original sources

bioRxiv2022

Shaping the Genome via Lengthwise Compaction, Phase Separation, and Lamina Adhesion

The link between genomic structure and biological function is yet to be consolidated, it is, however, clear that physical manipulation of the genome, driven by the activity of a variety of proteins, is a crucial step. To understand the consequences of the physical forces underlying genome organization, we build a coarse-grained polymer model of the genome, featuring three fundamentally distinct classes of interactions: lengthwise compaction, i.e., compaction of chromosomes along its contour, self-adhesion among epigenetically similar genomic segments, and adhesion of chromosome segments to the nuclear envelope or lamina. We postulate that these three types of interactions sufficiently represent the concerted action of the different proteins organizing the genome architecture and show that an interplay among these interactions can recapitulate the architectural variants observed across the tree of life. The model elucidates how an interplay of forces arising from the three classes of genomic interactions can drive drastic, yet predictable, changes in the global genome architecture, and makes testable predictions. We posit that precise control over these interactions in vivo is key to the regulation of genome architecture.

biophysics↗

bioRxiv2021

SMOG 2 and OpenSMOG: Extending the limits of structure-based models

Applying simulations with structure-based (G[o]-like) models has proven to be an effective strategy for investigating the factors that control biomolecular dynamics. The common element of these models is that some (or all) of the intra/inter-molecular inter-actions are explicitly defined to stabilize an experimentally-determined structure. To facilitate the development and application of this broad class of models, we previously released the SMOG 2 software package. This suite allows one to easily customize and distribute structure-based (i.e. SMOG) models for any type of polymer-ligand system. Since its original release, user feedback has driven the implementation of numerous enhancements. Here, we describe recent extensions to the software and demonstrate the capabilities of the most recent version, SMOG v2.4. Changes include new tools that aid user-defined customization of force fields, as well as an interface with the OpenMM simulation libraries (OpenSMOG v1.0). To illustrate the utility of these advances, we present several applications of SMOG2 and OpenSMOG, which include systems with millions of atoms, long polymers and explicit ions. We also highlight how one can incorporate non-structure-based (e.g. AMBER-based) energetics to define a hybrid class of models. The representative applications include large-scale rearrangements of the SARS-CoV-2 Spike protein, the HIV-1 capsid in the presence of explicit ions, and crystallographic lattices of ribosomes and proteins. In summary, SMOG 2 and OpenSMOG provide robust support for researchers who seek to apply structure-based models to large and/or intricate biomolecular systems.

biophysics↗

bioRxiv2020

Exploring Chromosomal Structural Heterogeneity AcrossMultiple Cell Lines

We study the structural ensembles of human chromosomes across different cell types. Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using a combination of machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. The chromosomal structures obtained in silico are quantitatively consistent with those obtained through microscopy as well as DNA-DNA proximity ligation assays. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make transitions between a closed conformation and an open dumbbell conformation. This conformational transition appears to be consistent with a two-state process with an effective free energy cost of about four times the effective information theoretic temperature. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. Genetically identical but epigenetically distinct cell types appear to rearrange their respective structural ensembles to expose segments of transcriptionally active chromatin, belonging to the A genomic compartment, towards the surface of the chromosome, while inactive segments, belonging to the B compartment, move to the interior. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories.

biophysics↗

bioRxiv2017

Asian lineage of Zika virus RNA pseudoknot may induce ribosomal frameshift and produce a new neuroinvasive protein ZIKV-NS1’

Zika virus (ZIKV) is a threat to humanity, and understanding its neuroinvasiveness is a major challenge. Microcephaly observed in neonates in Brazil is associated with ZIKV that belongs to the Asian lineage. What distinguishes the neuroinvasiveness between the RNA lineages from Asia and Africa is still unknown. Here we identify an aspect that may explain the different behavior between the two lineages. The distinction between the two groups is the occurrence of an alternative protein NS1 (ZIKV-NS1), which happens through a pseudoknot in the virus RNA that induces a ribosomal frameshift. Presence of NS1 protein is also observed in other Flavivirus that are neuroinvasive, and when NS1 production issuppressed, neuroinvasiveness is reduced.1 This evidence gives grounds to suggest that the ZIKV-NS1 occurring in the Asian lineage is responsible for neuro-tropism, which causes the neuro-pathologies associated with ZIKV infection, of which microcephaly is the most dev astating. The existence of ZIKV-NS1, which only exists in the Asian lineage, was inferred through bioinformatic methods, and it has yet to be experimentally observed. If its occurrence is confirmed, it will be a potential target in fighting the neuro-diseases associated with ZIKV.

epidemiology↗