Research
The role of protein conformational equilibrium in the biological function
Our group used nuclear spin relaxation to study protein dynamics in multiple timescales. Protein function is not determined uniquely by the most populated conformational state, but by knowing all the thermally accessible conformational states. To fully understand the biological function of a protein it is necessary to understand the energy landscape and conformational equilibrium. We characterize the conformational landscape of important biological targets and, with this, we aim to describe details of the mechanisms of interaction and allostery.
Life is mediated by protein interactions. Proteins evolved to interact with multiple partners. During evolution the selection criteria was not high stability and presence of structure, but rather intermediate stability and capacity of interaction with cellular partners. The understanding of the interaction-code of life, we need to describe protein conformational equilibrium. NMR is a powerful tool for this goal.
Using NMR, our group is studying important biological targets:
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1 – Dengue and Zika virus capsid protein.
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We described the ability of Dengue virus capsid protein to interact with lipid droplets. We mapped the interaction site and described the importance of dynamics. The anchoring of the capsid protein to hydrophobic interfaces in the cell is essential for the capsid assembly.
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We solved the structure of Zika virus capsid protein and described its dynamics in solution. We determined that α-helix 1 is a hotspot for evolutionary adaptation to different cells. Its position and orientation regulate the ability to recognize hydrophobic interfaces.
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We are working on the structure and dynamical properties of the capsid of dengue virus. The structure of the capsid of Flavivirus is still unknown.
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2- The description of dynamical elements in proteins:
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The water cavity of thioredoxins, which is essential for its mechanism of disulfide reduction.
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We study the structure and dynamics of plant defensins. They present a canonical ab cysteine stabilized protein folding, which is extensively crosslinked by disulfide bonds. Despite this, defensins presents complex dynamics. We could correlate its dynamics properties with the fact that most hydrophobic residues are exposed to the solvent. Yet, they are highly soluble and stable. Based on this observation, a dynamical folding element called hydrophobic surface clusters. We have the goal to understand how a hydrophobic residue exposed to the solvent is protected by nearby hydrophilic side-chains and its solvation.
3- The mechanism of transnitrosylation and thiolation of mammalians thioredoxins. Thioredoxin is able to transfer nitric oxide (NO), which mediates important biological effects, such as the regulation of apoptosis. The understanding of the mechanism of transnitrosylation of thioredoxin is essential for many pathways in the cell.
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4- Dynamics of multidomain proteins:
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HSP-40 co-chaperones
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Growth factor receptor-bound protein 2 (Grb2), an adaptor protein involved in signal transduction.
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M2-1 and Matrix protein of Syncytial Respiratory Pulmonary Virus
5- We are also studying other systems, such as Mycobacterium tuberculosis essential enzymes, such as Ribose5-Phosphate isomerase type B (R5PB) and mtFKPB, a prolyl isomerase.