2-7 June 2019
Simon Fraser University
America/Vancouver timezone
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Interplay between native state topology and sequence in two-state protein folding

Jun 4, 2019, 9:30 AM
HC 114 (Simon Fraser University)

HC 114

Simon Fraser University

Oral (Non-Student) / Orale (non-étudiant(e)) Physics in Medicine and Biology / Physique en médecine et en biologie (DPMB-DPMB) T1-8 Topics in medical physics and biophysics (DPMB) | Sujets en physique médicale et biophysique (DPMB)


Stefan Wallin (Memorial University of Newfoundland)


One of the outstanding questions in protein folding is why the folding into some native state topologies, e.g. all-$\alpha$ folds, are more sensitive to sequence variations than other, more nonlocal protein folds, such as all-$\beta$ folds? To explore this question, we design and study three 35-54 amino acid sequences within a coarse-grained sequence-based model and show that they fold spontaneously into stable 3$\alpha$, 4$\beta+\alpha$ and $\beta$-barrel folds, respectively. Their thermodynamic behaviors, calculated using Monte Carlo techniques, exhibit features in line with experimental data including rank order of folding cooperativity and temperature-driven Hammond shifts of transition states. Using a novel generalized ensemble algorithm (A. Aina and S. Wallin, Journal of Chemical Physics 147, 095102, 2017) we then systematically study the effect of single- and double-point mutations on each of the three proteins. In total, $>$2,000 mutants are studied. We find that the proteins respond to sequence variations in a topology-dependent manner. In particular, the folding landscape of the $\beta$-barrel protein is the least perturbed of the three proteins, explaining previously observed mutational robustness of non-local folds. Moreover, we observe a link between the size of conformational fluctuations of these proteins and the divergence exhibited by their respective mutants. One consequence of such a link is that proteins with diverse folding pathways might be more sensitive to sequence variations than proteins with restricted folding pathways.

Primary authors

Stefan Wallin (Memorial University of Newfoundland) Mr Daniel Trotter (University of Ottwawa)

Presentation materials