A5006329960- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Chromosomal and Genetic Variations
- Redox biology and oxidative stress
- Epigenetics and DNA Methylation
- Free Radicals and Antioxidants
- Plant Molecular Biology Research
- Sulfur Compounds in Biology
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- Fluorine in Organic Chemistry
- Metal-Catalyzed Oxygenation Mechanisms
- Chromatin Remodeling and Cancer
- Protein Structure and Dynamics
- Cancer-related gene regulation
- RNA Interference and Gene Delivery
- Heat shock proteins research
- Genetics, Bioinformatics, and Biomedical Research
- RNA and protein synthesis mechanisms
- Biochemical effects in animals
- Organic Chemistry Cycloaddition Reactions
- Microbial Metabolic Engineering and Bioproduction
- Electron Spin Resonance Studies
- Genetics and Neurodevelopmental Disorders
- Organoselenium and organotellurium chemistry
Simons Foundation
2023-2025
New York University
2019-2025
Universidad de la República
2013-2018
The biomolecular modeling field has flourished since its early days in the 1970s due to rapid adaptation and tailoring of state-of-the-art technology. resulting dramatic increase size timespan simulations outpaced Moore's law. Here, we discuss role knowledge-based versus physics-based methods hardware software advances propelling forward. This outreach suggests a bright future for modeling, where theory, experimentation simulation define three pillars needed address scientific biomedical challenges.
Two-cysteine peroxiredoxins (Prx) have a three-step catalytic cycle consisting of (1) reduction peroxide and formation sulfenic acid on the enzyme, (2) condensation with thiol to form disulfide, also known as resolution, (3) disulfide by reductant protein. By following changes in protein fluorescence, we studied pH dependence reaction 2 human 1, 2, 5 Salmonella typhimurium AhpC obtained rate constants for pKa values involved each system. The observed constant spans orders magnitude, but all...
Nucleosomes form heterogeneous groups in vivo, named clutches. Clutches are smaller and less dense mouse embryonic stem cells (ESCs) compared to neural progenitor (NPCs). Using coarse-grained modeling of the pluripotency Pou5f1 gene, we show that genome-wide clutch differences between ESCs NPCs can be reproduced at a single gene locus. Larger formation is associated with changes compaction internucleosome contact probability fiber. single-molecule tracking (SMT), further core histone protein...
Human peroxiredoxin-5 (PRDX5) is a thiol peroxidase that reduces H2O2 10(5) times faster than free cysteine. To assess the influence of two conserved residues on reactivity critical cysteine (C47), we determined reaction rate constants PRDX5, wild type (WT), T44V and R127Q with one substrate electrophile (H2O2) nonspecific (monobromobimane). We also studied corresponding reactions low molecular weight (LMW) thiolates in order to construct framework against which could compare our proteins....
The complex role of linker histone (LH) on chromatin compaction regulation has been highlighted by recent discoveries the effect LH binding variability and isoforms genome structure function. Here we examine two variants variable modes fibers. Our mesoscale modeling considers oligonucleosomes with H1C H1E, bound in three different off-dyad modes, spanning densities (0.5–1.6 per nucleosome), over a wide range physiologically relevant nucleosome repeat lengths (NRLs). studies reveal an...
We reassess progress in the field of biomolecular modeling and simulation, following up on our perspective published 2011. By reviewing metrics for field's productivity providing examples success, we underscore productive phase field, whose short-term expectations were overestimated long-term effects underestimated. Such successes include prediction structures mechanisms; generation new insights into activity; thriving collaborations between experimentation, including experiments driven by...
Abstract Typical 2-Cys Peroxiredoxins (2-Cys Prxs) reduce hydroperoxides with extraordinary rates due to an active site composed of a catalytic triad, containing peroxidatic cysteine (C P ), Arg, and Thr (or Ser). Prx are involved in processes such as cancer; neurodegeneration host-pathogen interactions. During catalysis, Prxs switch between decamers dimers. Analysis structures the fully folded (but not locally unfolded) form revealed highly conserved, non-conventional hydrogen bond (CH-π)...
A longstanding hypothesis is that chromatin fiber folding mediated by interactions between nearby nucleosomes represses transcription. However, it has been difficult to determine the relationship local compaction and transcription in cells. Further, global changes diameters have not observed, even interphase mitotic chromosomes. We show an increase range of inter-nucleosomal contacts quiescent yeast drives fibers genome-wide. Unlike actively dividing cells, cells require a basic patch...
Transcription factors (TF) bind to chromatin and regulate the expression of genes. The pair Myc:Max binds E-box regulatory DNA elements throughout genome control transcription a large group specific We introduce an implicit modeling protocol for binding mesoscale fibers at nucleosome resolution determine TF effect on architecture shed light into its mechanism gene regulation. first different locations show how it can direct fiber folding formation microdomains, this depends linker length....
The formation of condensed heterochromatin is critical for establishing cell-specific transcriptional programs. To reveal structural transitions underlying in maturing mouse rod photoreceptors, we apply cryo-EM tomography, AI-assisted deep denoising, and molecular modeling. We find that chromatin isolated from immature retina cells contains many closely apposed nucleosomes with extremely short or absent nucleosome linkers, which are inconsistent the typical two-start zigzag folding. In...
Histone modifications play a crucial role in regulating chromatin architecture and gene expression. Here we develop multiscale model for incorporating methylation our nucleosome-resolution physics-based to investigate the mechanisms by which H3K9 H3K27 trimethylation (H3K9me3 H3K27me3) influence structure regulation. We apply three types of energy terms this purpose: short-range potentials are derived from all-atom molecular dynamics simulations wildtype methylated chromatosomes, revealed...
Abstract Chromatin structure, dynamics, and function are being intensely investigated by a variety of methods, including microscopy, X‐ray diffraction, nuclear magnetic resonance, biochemical crosslinking, chromosome conformation capture, computation. The modeling helps interpret experimental data generate configurations mechanisms related to the three‐dimensional organization genome. Experimental contact maps, in particular, as obtained capture increasing interest due their implications on...
Transcription factors (TF) bind to chromatin and regulate the expression of genes. The pair Myc:Max binds E-box regulatory DNA elements throughout genome control transcription a large group specific We introduce an implicit modeling protocol for binding mesoscale fibers at nucleosome resolution determine TF effect on architecture shed light into its mechanism gene regulation. first different locations show how it can direct fiber folding formation microdomains, this depends linker length....
Modeling and simulation have quickly become equivalent pillars of research along with traditional theory experimentation. The growing realization that most complex phenomena interest span many orders spatial temporal scales has led to an exponential rise in the development application multiscale modeling over past two decades. In this perspective, associate editors International Journal for Multiscale Computational Engineering their co-workers illustrate current applications respective...
Abstract Motivated by experiments connecting linker histone (LH) deficiency to lymphoma progression and retinal disorders, we study mesoscale chromatin modeling how LH density (ρ) induces gradual, as well sudden, changes in architecture the process depends on DNA length, binding dynamics mode, salt concentration, tail modifications, combinations of ρ length. We show that tightly regulates overall shape compaction fiber, triggering a transition from an irregular disordered state compact...
In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound chromosomes. This organization allows regulatory elements in the genome, often distant from each linear DNA, to interact facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC-binding factor (CTCF) one of major components TAD formation responsible for recruiting a partner protein, cohesin, perform loop extrusion proper within TADs. Because single-residue...