title: Structural and energetic determinants of co-translational folding.
abstract: We performed extensive lattice Monte Carlo simulations of ribosome-bound stalled nascent chains (RNCs) to explore the relative roles of native topology and non-native interactions in co-translational folding of small proteins. We found that the formation of a substantial part of the native structure generally occurs towards the end of protein synthesis. However, multi-domain structures, which are rich in local interactions, are able to develop gradually during chain elongation, while those with proximate chain termini require full protein synthesis to fold. A detailed assessment of the conformational ensembles populated by RNCs with different lengths reveals that the directionality of protein synthesis has a fine-tuning effect on the probability to populate low-energy conformations. In particular, if the participation of non-native interactions in folding energetics is mild, the formation of native-like conformations is majorly determined by the properties of the contact map around the tethering terminus. Likewise, a pair of RNCs differing by only 1-2 residues can populate structurally well-resolved low energy conformations with significantly different probabilities. An interesting structural feature of these low-energy conformations is that, irrespective of native structure, their non-native interactions are always long-ranged and marginally stabilizing. A comparison between the conformational spectra of RNCs and chain fragments folding freely in the bulk reveals drastic changes amongst the two set-ups depending on the native structure. Furthermore, they also show that the ribosome may enhance (up to 20%) the population of low energy conformations for chains folding to native structures dominated by local interactions. In contrast, a RNC folding to a non-local topology is forced to remain largely unstructured but can attain low energy conformations in bulk.
authors.affiliation: Centro de Física da Matéria Condensada and Departamento de Física, Universidade de Lisboa, Av. Prof. Gama Pinto 2, 1649-003 Lisboa, Portugal.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Krobath
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
authors.forename: Patrícia F N
authors.initials: PF
authors.lastname: Faísca
mesh_terms: D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins