Biology subjects

Oliveira Junior, A. B.

Publications and source records attributed to Oliveira Junior, A. B..

3 recordsLinked to original sources

bioRxiv2022

Structural Reorganization and Relaxation Dynamics of Axially Stressed Chromosomes

Micromechanical studies of mitotic chromosomes have revealed them to be remarkably extensible objects and informed early models of mitotic chromosome organization. We use a data-driven, coarsegrained polymer modeling approach, capable of generating ensembles of chromosome structures that are quantitatively consistent with experiments, to explore the relationship between the spatial organization of individual chromosomes and their emergent mechanical properties. In particular, we investigate the mechanical properties of our model chromosomes by axially stretching them. Simulated stretching led to a linear force-extension curve for small strain, with mitotic chromosomes behaving about ten-fold stiffer than interphase chromosomes. Studying the relaxation dynamics we found that chromosomes are viscoelastic solids, with a highly liquid-like, viscous behavior in interphase that becomes solid-like in mitosis. This emergent mechanical stiffness in our model originates from lengthwise compaction, an effective potential capturing the activity of loop-extruding SMC complexes. Chromosomes denature under large strains via unraveling, which is characterized by opening of large-scale folding patterns. By quantifying the effect of mechanical perturbations on the chromosomes structural features, our model provides a nuanced understanding of in vivo mechanics of chromosomes.

biophysics↗

bioRxiv2021

Examining the Ensembles of Amyloid-β Monomer Variants and their Propensities to Form Fibers Using an Energy Landscape Visualization Method

The amyloid-{beta} (A{beta}) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to A{beta}40 and A{beta}42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimers disease (AD). Experiments have shown that even though the natural abundance of A{beta}42 is smaller than that for A{beta}40, the A{beta}42 is more aggregation-prone compared to A{beta}40. Moreover, several single-point mutations are associated with early-onset forms of AD. This work analyzes coarse-grained AWSEM simulations of normal A{beta}40 and A{beta}42 monomers, along with six single-point mutations associated with early on set disease. We analyzed the simulations using the Energy Landscape Visualization Method (ELViM), a reaction coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino-acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.

biophysics↗

bioRxiv2021

Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms

Intrinsically disordered proteins (IDPs) lack a rigid 3D structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction coordinates presents a daunting challenge. Here, our newly developed Energy Landscape Visualization Method (ELViM), a reaction coordinate-free approach, shows its prime application to explore frustrated energy landscapes of an intrinsically disordered protein, Prostate-Associated Gene 4 (PAGE4). PAGE4 is a transcriptional coactivator that potentiates the oncogene c-Jun. Two kinases, namely HIPK1 and CLK2, phosphorylate PAGE4 generating variants phosphorylated at different serine/threonine residues (HIPK1-PAGE4 and CLK2-PAGE4, respectively) with opposing functions. While HIPK1-PAGE4 predominantly phosphorylates Thr51 and potentiates c-Jun, CLK2-PAGE4 hyper-phosphorylates PAGE4 and attenuates transactivation. To understand the underlying mechanisms of conformational diversity among different phosphoforms, we have analyzed their atomistic trajectories simulated using AWSEM forcefield and the energy landscapes were elucidated using ELViM. This method allows us to identify and compare the population distributions of different conformational ensembles of PAGE4 phosphoforms using the same effective phase space. The results reveal a predominant conformational ensemble with an extended C-terminal segment of WT PAGE4, which exposes a functional residue Thr51, implying its potential of undertaking a fly-casting mechanism while binding to its cognate partner. In contrast, for HIPK1-PAGE4, a compact conformational ensemble enhances its population sequestering phosphorylated-Thr51. This clearly explains the experimentally observed weaker affinity of HIPK1-PAGE4 for c-Jun. ELViM appears as a powerful tool especially to analyze the highly-frustrated energy landscape representation of IDPs where appropriate reaction coordinates are hard to apprehend.

biophysics↗