Physics and Chemistry of Biological Systems

Characterization of dense phases of biopolymers
personP.I. C. Micheletti

In our group we develop and apply theoretical and computational techniques aimed at characterizing the entanglement of dense phases of long biopolymers, particularly DNA. In all organisms, from eukaryotic cells to bacteria and viria, the DNA filaments carrying the genomic information are subject to a very high degree of spatial confinement. The high packing density must be achieved avoiding the formation of entanglements that would be incompatible with the correct biological processing of the genomic material. The central focus of our research is the elucidation of the physical mechanisms that are co-opted in living systems to avoid the excessive geometrical and topological entanglement of DNA filaments.

Elucidating the structure-function relationship in enzymes
personP.I. C. Micheletti

Part of the activity of our group is aimed at developing and applying coarse-grained models for describing the large-scale internal dynamics of proteins and then compare it across superfamilies of enzymes with similar function but different fold.

The long-term objective is to use the dynamics-based comparative scheme to advance the understanding of the structure-function relationship in proteins. The approach is similar in spirit to the classical studies on the sequence-structure relationship. The availability of both sequence and structure comparative (alignment) methods has clarified that, because of either evolutionary conservation or convergence, proteins with different primary chemical sequences can adopt similar native structures.

We have developed a novel set of tools that allows for addressing an analogously challenging question: can proteins with different native fold exhibit similar functionally-oriented movements? What underlying evolutionary mechanisms can we highlight with this scheme. See ref. to learn more about it.

Simulating rare events in biological systems
personP.I. A. Laio

In our group we work at improving techniques for simulating rare events, in order to make them suitable for studying realistic processes. Particular attention is devoted to metadynamics , an algorithm that has been successfully applied in several different fields, ranging from chemistry to crystal structure prediction to biophysics. We are presently applying this methodology for complex transitions in biomolecules. In these cases the number of "interesting" variables that one has to sample and explore is intrinsically very large. This has led to develop a new method, bias-exchange metadynamics, that allows the simultaneous reconstruction of a free energy in several variables. His approach allows predicting the folded state and the folding time of small proteins (up to 40 amino acids) described with an accurate potential, in which the water is described explicitly (see Foding Folding for more details). The same approach can be used for studying, also with a very accurate potential, the binding process of drugs to their target protein, predicting with great accuracy the binding affinity (see Docking for more details).

Simulation of small ribonucleic acid (RNA)
personP.I. G. Bussi

The goal of this research line is to study the folding and the conformational transitions of small ribonucleic acid (RNA) molecules using advanced accelerated-sampling methods and developing new ad hoc techniques. Currently, in collaboration with Dr. Francesco Colizzi, we are studying small RNA motifs of increasing complexity (helices, hairpins and pseudoknots), providing information complementary to that directly obtainable from experiments, and using the experiments as a validating tool of our models and methodologies.

PLUMED  Development
personP.I. G. Bussi

PLUMED is a plugin which implements several methods for accelerated sampling and can be used in combination with several molecular dynamics codes. More information can be found here.

Structure and dynamics of interphase chromosomes
personP.I. A. Rosa

Understanding how genomic DNA folds inside the nuclei of eukaryotic cells is one of the most active research fields in modern cell biology, due to its connections with important processes such as gene expression, gene regulation and DNA replication. Yet, most of the physico-chemical details remain unknown. There is now compelling evidence that the large-scale organisation of the genomes mirrors the underlying polymer structure of long, entangled fibers of DNA.

Our research focus on the development and implementation of theoretical and numerically-efficient (multi-scale) tools, in order to exploit the Physics underlying genome structure in eukaryotes.

Molecular Mechanisms of Diseases and Drugs
personP.I. A. Magistrato

(1) DNA Damage Recognition and Repair:
In this respect we are currently studying the molecular recognition mechanism of repair enzymes (i.e. Uracil-DNA-Glycosylase (in collaboration with Dr. G. Bussi, SISSA) and photolyases) aiming at unveiling the principles of DNA damage recognition, one of the most fascinating open question in biology. In addition, we have recently focused on the study of inorganic molecules (Rh metalloinsertors) that selectively recognize DNA mismatches, cleaving the DNA filament, and being active as anticancer drugs in vivo.

(2) Metal Based Anticancer Drugs and Devices:
The most characterized metal drug is cisplatin, routinely used on the clinics. In recent years we have studied the structural properties of platinated drugs/DNA adducts. Next studies will be aimed at understanding the interactions between platinated drug-DNA/repair enzymes to shed light on the resistance mechanisms to cisplatin. In collaboration with the experimental group of Prof. D. Bonifazi, University of Namur, Belgium, we have recently focused in the design and synthesis of magnetic nanotubes functionalized with tumoral biomarkers to be employed in the specific recognition of cancer cells.

(3) Osteoarticolar disesases:
In collaboration with the University of Siena and the University of Florence we are focusing in the assembly of hydrogels and calcium phosphate (CP) nanocrystals functionalized with synthetic inhibitors of matrix metalloproteinase (MMPs) enzymes with the aim of synthesizing and characterizing engineered materials to counteract the tissues degradation provoked by MMPs, which results in the osteoarticolar diseases.

Enzymatic and biomimetic catalysis
personP.I. A. Magistrato

(1) Molecular mechanisms of metal containing enzymes:
Aromatase cytocrome P450 is an iron containing enzyme of crucial biological and pharmacological relevance as it is the only enzyme in vertebrates to catalyze the biosynthesis of all estrogens from androgens. Aromatase inhibitors are, therefore, of paramount importance in the therapy of estrogen dependent breast cancer. We have recently started to investigate the mechanism of aromatase to understand its unique catalytic properties and the molecular basis for its high androgenic specificity. This information may be of help for developing next generation aromatase inhibitors to be employed in anticancer therapy.

(2) Biomimetic catalysts:
An increase in global energy demand as well as the issues related to the global climate change have made nowadays the search of renewable energy one of challenge of science. As small part of my research activity is focused in the study of inorganic biomimetic catalysts that can generate hydrogen from water with high efficiency. This catalyst would mimic the work performed by hydrogenase enzymes in Nature.