Program

I.11 -- Invited, IWTCP-3

Date: Wednesday, 29 July 2015

Time: 11h05 - 11h40

Codon positions that strongly influence cotranslational folding are far from equilibrium: A framework for controlling nascent-protein folding

Edward O'Brien

Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA

Synonymous codon substitutions change the translation rate at specific positions within an mRNA’s coding sequence without changing the encoded protein’s amino acid sequence and can alter a nascent protein’s ability to cotranslationally fold and function. The physical rules governing why synonymous mutations at some codon positions can have a much greater impact on nascent protein folding than others remain unknown. Here, we introduce a framework that allows for the control of nascent chain folding during translation through the rational design of mRNA sequences using synonymous codons. We test this framework in silico and find it provides optimal mRNA sequences to control the simulated, cotranslational folding of a protein in a user-prescribed manner. With this approach we discover the rules governing the positioning and impact of critical codons. First, the position of a critical codon depends on the cotranslational profile, which is the probability of a protein populating different conformational states as a function of the nascent chain length. As a consequence, different cotranslational profiles can have different critical codon positions, even though the encoded protein may be the same. Second, the impact of a mutation at a critical codon position is proportional to how far from equilibrium the cotranslational folding curve is at that and subsequent codon positions. Our results show that a cotranslational profile’s deviation from equilibrium, its sensitivity to single-point mutations, and its mRNA-sequence degeneracy are inter-related, and that each of these factors has direct implications for nascent protein behavior, critical codon positions and mRNA sequence evolution.

Presenter: Edward O'Brien