Speaker
Description
Computer modeling has been quite successful in predicting protein fold from amino acid sequence using similarity patterns in the growing amount of data from structural biology experiments. Moreover, the dynamics of the folding process itself has been simulated in the case of small proteins. The energy landscape of complex protein systems has been usually described by empirical physical models (force fields). In contrast, more accurate quantum-chemical (QM) models have been extensively used to study chemistry in the truncated active sites of the enzymes. In would be desirable to use the accurate QM methods to study protein folding, however, such models are still computationally very demanding. In our recent study, we came with an idea to divide the protein into capped tripeptides, which represent a reasonable model of an amino acid in its local environment that can be used for extensive conformational sampling and QM free energy calculations. When we compare conformer ensembles of tripeptide sequences that are found predominantly in one type of secondary structure (alpha-helix or beta-sheet), we see an energetic preference to form hydrogen bonds typical for the respective secondary structure type. This propensity is further modulated by the polarity of the environment. In addition, we have shown that tripeptide conformers extracted from experimental structures must be stabilized by significant amount of energy coming from the protein context. When an empirical force field is used for energy evaluation, the outcome is far less conclusive. These results led us to the central idea of the present study – can we identify the folding initiation sites by dividing the protein of interest into tripeptides and calculating their relative free energy within the unbiased conformer ensemble? We test this idea on well-studied stable miniprotein folds. In line with existing experimental and theoretical studies of protein folding mechanisms we see that the tripeptides with the lowest energy relative to the most stable conformer of the respective isolated tripeptide lie within alpha-helices and in beta-turns. This implies that the protein folding is initiated either by alpha-helix formation, or by aligning two extended segments connected by the beta-turn toward beta-sheet formation. The tripeptides within the beta-sheets show the highest interaction energy with the rest of the protein. Furthermore, we observe that these highly strained but highlt interaction regions are those conserved by evolution. Our results indicate that the evolution has conserved the residues contributing for overall thermodynamic stability at the cost of lower local stability. In contrast, the segments connecting these crucial regions were evolutionary optimized to facilitate the folding dynamics.
