Computational Molecular Biophysics

My focus is the physics and chemistry of biomolecules, including their structure, dynamics, thermodynamics, and statistical mechanics, addressed theoretically and through computer simulations. The main goal is to understand and quantify the molecular mechanisms that govern the function of biomolecules and their complexes, either in normal or pathological conditions. These include macromolecules, such as proteins and nucleic acids, and small molecular species, such as drugs, neurotransmitters, or imaging probes. Their collective and cooperative interactions in the cell are fundamental for the function of living organisms, and perturbations of the delicate balance of intermolecular forces may lead to disease.

My work comprises three interrelated areas:

(A) Molecular recognition and association/dissociation mechanisms: The aqueous medium controls all the properties of biomolecules, from reaction mechanisms of small chemical species to the structure and thermodynamic of macromolecules. The composition of the medium plays a central role in the kinetics and dynamics of molecular encounters, including drug-protein binding, ultimately controlling the behavior of metabolic pathways and protein-protein interaction networks, multimeric complexation, and aggregation. I am particularly interested in the properties of aqueous interfaces because they are involved in almost all process of biological relevance, including molecular recognition. Targeting specific interfaces can change the behavior of major signal transduction pathways. Biointerfaces also determine the effects of the solution species (ions, cosolutes, osmolytes, etc) both in the intra- and extracellular milieu, and thus control the association and dissociation mechanisms at the molecular level.

These studies often require the development of new computational methods for efficient simulations and analysis (C, below). This is so because molecular processes in biology involve time and size scales that span several orders of magnitude, from the purely microscopic (atomistic) to the mesoscopic and macroscopic (i.e., thermodynamic, hydrodynamic) levels of description. Since experiments are difficult to carry out and molecular interpretations often elusive, I perform simulations to better understand the underlying mechanisms, and use the insight gained from these 'experiments' as guidelines for the development of physics-based models and algorithms.

(B) Macromolecular complexation, aggregation, and self-assembly: I am interested in the microscopic origin of macroscopic organization and formation of spatial structures and temporal patterns in systems of biological interest. Although this is a basic problem that concerns many systems in nature, its relevance in biology covers a broad range of phenomena, from complex molecular processes, such as the self-assembly of virus particles, to macroscopic cellular processes, such as those involved in the cell cycle, to events at the level of tissues and organs. Molecular inisght into such phenomena require dealing with multispecies multiprotein systems for which reliable computational approaches are either lacking or inefficient. Multiscale simulations coupled with biophysical and mathematical modeling are used to address these problems, which may help to rationally intervene to control biochemical processes and ultimately fight disease. Areas of increasing interest in biomedicine is the study of protein-protein interaction networks and the ability to control and modify their structures by targeting specific hubs and vertices (e.g., with small, drug-like compounds or with synthetic macro-cyclic peptides); the study of functionalized nanoparticles and other biomimetic nanodevices to target cells and tissues; of nanocrystallization of drugs for controlled drug delivery; and of biomineralization, e.g., mineral deposition in body tissues, such as lymph nodes and arteries, which leads to serious pathologies. Computational modeling and simulations can offer insight into such phenomena and suggest strategies to regulate them.

(C) Methods development: An important aspect of my work is the development of efficient computational methods and algorithms to tackle biological and biomedical problems at increasing levels of molecular complexity. I carry out simulation with well established techniques, including molecular dynamics and Monte Carlo, as well as ad hoc adaptations of these and other methods, often motivated by the needs to address specific experimental problems. I use molecular mechanics force fields to study the thermodynamics and structure of macromolecules, and quantum mechanics/molecular mechanics hybrid approaches to study problems where a higher level of theory is needed, e.g., to describe chemical reactions, including proton transfer.
 



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