Abstract:
:Understanding how polypeptides can efficiently and reproducibly attain a self-entangled conformation is a compelling biophysical challenge that might shed new light on our general knowledge of protein folding. Complex lassos, namely self-entangled protein structures characterized by a covalent loop sealed by a cysteine bridge, represent an ideal test system in the framework of entangled folding. Indeed, because cysteine bridges form in oxidizing conditions, they can be used as on/off switches of the structure topology to investigate the role played by the backbone entanglement in the process. In this work, we have used molecular dynamics to simulate the folding of a complex lasso glycoprotein, granulocyte-macrophage colony-stimulating factor, modeling both reducing and oxidizing conditions. Together with a well-established Gō-like description, we have employed the elastic folder model, a coarse-grained, minimalistic representation of the polypeptide chain driven by a structure-based angular potential. The purpose of this study is to assess the kinetically optimal pathways in relation to the formation of the native topology. To this end, we have implemented an evolutionary strategy that tunes the elastic folder model potentials to maximize the folding probability within the early stages of the dynamics. The resulting protein model is capable of folding with high success rate, avoiding the kinetic traps that hamper the efficient folding in the other tested models. Employing specifically designed topological descriptors, we could observe that the selected folding routes avoid the topological bottleneck by locking the cysteine bridge after the topology is formed. These results provide valuable insights on the selection of mechanisms in self-entangled protein folding while, at the same time, the proposed methodology can complement the usage of established minimalistic models and draw useful guidelines for more detailed simulations.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Perego C,Potestio Rdoi
10.1016/j.bpj.2019.05.025subject
Has Abstractpub_date
2019-07-23 00:00:00pages
214-228issue
2eissn
0006-3495issn
1542-0086pii
S0006-3495(19)30446-1journal_volume
117pub_type
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