Annual Report 2011
Research Highlights
BC Molecular Simulation António M. Baptista
baptista@itqb.unl.pt
Our group used computational simulation methods to perform the first extensive structural characterization of peptide dendrimers, which are tree-like synthetic molecules composed of standard and bifurcated amino acids. Often used as agents for catalysis, binding and drug delivery, their bio-compatibility and proteolytic resistance makes them promising biomedical targets. Their behavior should be largely determined by itheir three-dimensional structure, but all experimental attempts were unable to reveal any structural details, thus hindering their truly rational design. Our simulations indicated that, unlike globular proteins, none of the studied dendrimers favors a preferential folded structure, displaying instead a very high conformational diversity. Despite this lack of a folded structure, two clearly distinct behaviors were observed in terms of compactness. The analysis of conformational clusters indicated that the energy landscapes depicting their structural preferences are mostly flat, markedly contrasting with the funnel-like landscapes of proteins. This study shows that peptide dendrimers have a complex conformational behavior that cannot be easily inferred from their chemical formula. Together with available experimental data, molecular simulation studies can help to reveal the function-structure determinants of these molecules and lead to a more rational design. Filipe L.C.S., Machuqueiro M. and Baptista A.M. (2011) J Am Chem Soc, 133(13) 5042
BC Protein Biochemistry Folding & Stability Cláudio M. Gomes
gomes@itqb.unl.pt
The laboratory investigates the biology and biophysics of protein folding, an essential cellular process through which proteins acquire a functional conformation. Protein misfolding is a hallmark in several human diseases, and in recent years we have been investigating this process fromdifferent perspectives: protein aggregation mechanisms in neurodegeneration (toxic gain of function) and protein misfolding and destabilization in metabolic disease (loss of function). The latter include defects in fatty acid oxidation, a group of rare diseases in which genetic mutations inactivate key metabolic enzymes by affecting their biogenesis, stability and degradation. In these cases, small molecules with the ability to raise functional levels of the affected protein above the disease threshold have proven valuable tools for effective drug design. In 2011 we published a pioneer study showing that cell metabolites such as cofactors and substrates are stabilizers of enzymes affected in these folding disorders. We found that physiological concentrations of these small molecules resulted in a spectacular enhancement of enzyme stabilities and prevented inactivation during conditions simulating in vitro fever episodes. The relevance of these findings is two-fold. First, it contributes to understanding how proteins behave under conditions near those of cell physiology. Secondly, it points that substrate analogs and cofactor precursors (e.g. Vit B2) which recover proteins with inherited folding difficulties have the potential to become lead compounds for drug development. Lucas T.G. et al. (2011) BBA - Mol Basis Dis, 1812(12) 658
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