[2P-45*] Prediction of folding mechanisms of lysozyme and α-lactalbumin by an extended statistical mechanical model
Free energy landscapes of protein folding provide comprehensive understanding of folding pathways and intermediates. The Wako-Saitô-Muñoz-Eaton (WSME) model is a coarse-grained structure-based statistical mechanical model of proteins that can calculate folding free energy landscapes. The model has succeeded in predicting folding mechanisms of small proteins consistent with experiments. However, it cannot be applied to general large proteins because formation of non-local interactions early in the folding cannot be considered in the model. Here, we introduced virtual linkers representing specific non-local interactions and developed the extended WSME model. We applied this model to lysozyme and α-lactalbumin by introducing the virtual linkers at disulfide bonds and succeeded in theoretically deriving the folding free energy landscapes that are consistent with experimentally observed folding pathways. Although these proteins have different folding pathways depending on the derived species, the extended model can explain the subtle differences in the folding mechanisms. Moreover, based on the free energy landscape and contact energy, we developed a theoretical method for searching for the residues important in determining the folding pathways.