Evidence for Internal Friction in IDPs of the Calcitonin Peptide Family

Abstract

The rate at which Intrinsically Disordered Proteins (IDPs) undergo large conformational changes in solution is expected to substantially affect their function. The roughness in IDPs energy landscape can significantly slow down this diffusional dynamics, giving rise to internal friction. Both experiments and simulations of unfolded states of proteins show that compact states exhibit greater internal friction than denaturant-expanded states1,2. Yet it is unclear to what extent, and in which way, changes in a protein sequence may affect the internal friction. Using a nanosecond laser-pump spectroscopy technique we quantify the rate at which two ends of a polypeptide chain come into contact, while also quantifying the relative end-to-end distance (or compactness) of the chain. We compare these values for different IDPs of the Calcitonin peptide (Ct) family. Our previous studies showed that these IDPs populate highly compact states in near native conditions3,4 and become more expanded at increasing denaturant concentrations5,6. We find that, under conditions in which the end-to-end distances are the same, certain sequences exhibit significantly slower contact formation rates than others, indicating greater internal friction. As expected, such differences are apparent in water but not in denaturant. We experimentally investigate the possible causes for the observed sequence-dependence.1. Soranno, Andrea, et al. PNAS 2012; 109:17800-17806.2. Echeverria, Ignacia, et al. JACS 2014; 136:8708-8713.3. Vaiana, Sara M., et al. BIOPHYSICAL J 2009; 97:2948-2957.4. Sizemore, Sara M., et al. BIOPHYSICAL J 2013; 104:54A-55A.5. Sizemore, Sara M., et al. BIOPHYSICAL J 2014; 106:270A.6. Cope, Stephanie M., et al. BIOPHYSICAL J 2014; 106:687A.