In 2013, I obtained my B.Sc. in Chemistry from the University of Buenos Aires, Argentina. During that period I became interested in computational chemistry and performed in silico studies involving quantum mechanics and hybrid QM-MM calculations, focusing on the autoxidation reaction of myoglobin. Later on, I obtained my Ph.D. degree in Computational Biochemistry under the supervision of Prof. Adrián Turjanski, also at the University of Buenos Aires.
My Ph.D. thesis focused on developing computational methods for the discovery of new pharmaceutically relevant compounds, using cosolvent molecular probes to mimic protein-ligand binding. The method is currently being further applied on Mycobacterium tuberculosis and Covid-19 protein targets in search of hit compounds with low micromolar binding affinity. During my doctoral studies I performed stays at the University of Barcelona in the Computational Biology and Drug Design group lead by Prof. Xavier Barril, a pioneer in cosolvent molecular dynamics simulations of proteins.
In 2018, I was awarded a Fulbright Scholarship to perform a three month research stay in Prof. Stefano Forli´s group at The Scripps Research Institute in La Jolla, USA. The main objective of the project was to increase the capabilities of the AutoDock program to perform high throughput docking with biased methodologies. Finally, I joined the Molecular Modelling and Bioinformatics group led by Prof. Modesto Orozco at IRB Barcelona in 2018 to start a project in 3D genomics for the modelling of chromosome and whole nucleus structures.
3D genome modelling: from the interaction between pairs of chromosomes to the conformation of the whole nucleus
The general objective of the project is to develop an integrated multiscale strategy to unveil the 3D conformation of chromatin, spanning sizes from individual genes, through short fibers or whole chromosomes, to reach the complete nucleus from yeast and human cells. Variable conditions such as oxidative stress or DNA methylation, and different differentiation states and cell cycle stages are studied to analyze their effect on chromatin structure.
Chromosome and nucleus scale conformations are addressed with a top-down coarse-grained model, representing the DNA as a self-avoiding bead-spring chain where each monomer is a portion of DNA. The mesoscopic model aims to interpret and integrate several sources of experimental information, such as chromosome conformation capture techniques (e.g. Hi-C) and high resolution microscopy, among others, to predict and compare DNA conformational space in 3D. The resolution of the coarse-grained bead is defined by the resolution of the available Hi-C contact maps, typically from 1 to 100 kb. The contact data obtained from Hi-C and related techniques are transformed to spatial distances which guide the conformational sampling of the model. Furthermore, Hi-C derived distances are integrated with physical constraints such as distances between key genomic elements (telomeres, centromeres, or specific genes) obtained through high resolution optical microscopy (STORM), or global descriptors of the nucleus configuration such as sphericity, nuclear volume or density of genomic content. Finally, restraint-based molecular dynamics simulations are performed to derive relaxed 3D structures and study the dynamics of genomes in 3D.
At a lower size scale, integration of MNase-seq and Micro-C data, combined with simple physical models considering equilibrium DNA helical parameters are used to simulate nucleosome fibers at base pair resolution. Different approaches are being tried, e.g. Monte Carlo simulations of flexible linker DNA and rigid nucleosomes or Langevin dynamics using elastic network models, complemented with van der Waals and electrostatic terms.
In summary, we are developing a comprehensive and automatic way to obtain reliable 3D structures of genes, chromosomes and whole nucleus, which will provide through simulations a dynamic view of chromatin conformation in 3D space and time. In the end, correlations between multiscale structures at different levels of resolution, cellular conditions and transcriptional profiles will be attained to shed light on the chromatin structure to function relationship.