Biology subjects

Micheletti, C.

Publications and source records attributed to Micheletti, C..

4 recordsLinked to original sources

bioRxiv2018

Dynamics of supercoiled DNA with complex knots: large-scale rearrangements and persistent multi-strand interlocking

Knots and supercoiling are both introduced in bacterial plasmids by catalytic processes involving DNA strand passages. While the effects on plasmid organization has been extensively studied for knotting and supercoiling taken separately, much less is known about their concurrent action. Here, we use molecular dynamics simulations and oxDNA, an accurate mesoscopic DNA model, to study the kinetic and metric changes introduced by complex (five-crossing) knots and supercoiling in 2kbp-long DNA rings. We find several unexpected results. First, the conformational ensemble is dominated by two distinct states, differing in branchedness and knot size. Secondly, fluctuations between these states are as fast as the metric relaxation of unknotted rings. In spite of this, certain boundaries of knotted and plectonemically-wound regions can persist over much longer timescales. These pinned regions involve multiple strands that are interlocked by the cooperative action of topological and supercoiling constraints. Their long-lived character may be relevant for the simplifying action of topoisomerases.

biophysics↗

bioRxiv2017

From Sequence to Function: Coevolving Amino Acids Encode Structural and Functional Domains

Amino acids interactions within protein families are so optimized that the sole analysis of evolutionary co-mutations can identify pairs of contacting residues. It is also known that evolution conserves functional dynamics, i.e., the concerted motion or displacement of large protein regions or domains. Is it, therefore, possible to use a pure sequence-based analysis to identify these dynamical domains? To address this question, we introduce here a general co-evolutionary coupling analysis strategy and apply it to a curated sequence database of hundreds of protein families. For most families, the sequence-based method partitions amino acids into few clusters. When viewed in the context of the native structure, these clusters have the signature characteristics of viable protein domains: they are spatially separated but individually compact. They have a direct functional bearings too, as shown for various reference cases. We conclude that even large-scale structural and functionally-related properties can be recovered from inference methods applied to evolutionary-related sequences. The method introduced here is available as a software package and web server (http://spectrus.sissa.it/spectrus-evo_webserver).

bioinformatics↗

bioRxiv2016

How to fold intricately: using theory and experiments to unravel the properties of knotted proteins

Over the years, advances in experimental and computational methods have helped us to understand the role of thermodynamic, kinetic and active (chaperone-aided) effects in coordinating the folding steps required to achieving a knotted native state. Here, we review such developments by paying particular attention to the complementarity of experimental and computational studies. Key open issues that could be tackled with either or both approaches are finally pointed out.

biophysics↗

bioRxiv2016

Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization

Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge- based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina-associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling.

biophysics↗