Marta Filizola

Research

Computational Biophysics of Membrane Proteins

For more information, please visit the Filizola Laboratory website.

The overall goal of our research is to achieve a detailed mechanistic understanding of signal transduction processes triggered by molecular recognition by means of computational methodologies that range from bioinformatics to modeling and simulation. The strength of our research relies on the integration of these computational methodologies with collaborative experimental approaches to provide valuable mechanistic interpretations at the molecular level of the ligand-induced transmission of the signal to the inner side of the cell membrane. While our research is driven by the exploration and improvement of computational methods to characterize generalizable mechanisms of molecular recognition and signal transduction, we are excited by the contributions that our computational and modeling efforts make to the experimental field through the generation of new testable hypotheses. Current major research activities in the lab include:

1) Structural Aspects of Oligomerization in the Function of G Protein-Coupled Receptors (GPCRs): Considerable evidence has accumulated in recent years suggesting that GPCRs associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction, and lifetime of such receptor complexes in living cells remain topics of intense debate. We are currently designing computational strategies to assess the spatial and temporal organization of GPCRs in explicit lipid bilayers, their variability across receptor subtypes, and their possible modulation by ligands and/or cell-specific lipid compositions. These aspects need to be addressed to clarify the functional role of GPCR complexes.

2)  Exploration of Membrane Protein Processes Using Enhanced Sampling Methods: We are investigating new ways to efficiently explore the conformational space of GPCRs (both monomers and dimers/oligomers), and to generate novel testable hypotheses of molecular mechanisms underlying receptor function. Specifically, we are validating the efficiency of various enhanced sampling methods in predicting ligand-specific activated states and/or likely interfaces of oligomerization that agree with experimental data.

3)  Elucidation of integrin allostery and bidirectional signaling (in collaboration with Dr. Barry Coller at Rockefeller University): We are continuing our collaborative efforts to improve current understanding of the molecular mechanism(s) of αIIbβ3 integrin activation and ligand binding at an atomic scale. This information is essential to the discovery/design of more effective anti-thrombotic drugs and our teamwork has so far proven to be very successful in this direction.

4) Dynamic mechanisms of GPCRs targeted by drugs of abuse (in collaboration with Dr. Jonathan Javitch at Columbia University and Dr. Lakshmi Devi at MSSM): Our computational research takes advantage of cutting-edge developments in theory and experiments to obtain rigorous mechanistic insight, at an unprecedented level of molecular detail, into the structure, spatio-temporal organization, and dynamics of opioid receptors in the membrane, thus broadening current understanding of opioid receptor-biased agonism. Specifically, we will contribute structural and dynamic information regarding sparsely-populated states of opioid receptors that are currently impossible or difficult to retrieve experimentally, thereby generating testable hypotheses of how, at the molecular level, different opioids induce differential oligomerization and signaling, leading to the specific behavioral effects of the drugs. Experimental validation of these computational predictions, attained through long-standing collaborations, will advance our current understanding of fundamental basic mechanisms of opioid receptor function, and pave the way to novel therapeutic strategies against drug abuse and addiction.