Abstract
The dimensions of intrinsically disordered proteins (IDPs) are sensitive to small energetic-entropic differences between intramolecular and protein–solvent interactions. This is commonly observed on modulating solvent composition and temperature. However, the inherently heterogeneous conformational landscape of IDPs is also expected to be influenced by mutations that can (de)stabilize pockets of local and even global structure, native and non-native, and hence the average dimensions. Here, we show experimental evidence for the remarkably tunable landscape of IDPs by employing the DNA-binding domain of CytR, a high-sequence-complexity IDP, as a model system. CytR exhibits a range of structure and compactness upon introducing specific mutations that modulate microscopic terms, including main-chain entropy, hydrophobicity, and electrostatics. The degree of secondary structure, as monitored by far-UV circular dichroism (CD), is strongly correlated to average ensemble dimensions for 14 different mutants of CytR and is consistent with the Uversky–Fink relation. Our experiments highlight how average ensemble dimensions can be controlled via mutations even in the disordered regime, the prevalence of non-native interactions and provide testable controls for molecular simulations.
Highlights
The dimensions of intrinsically disordered proteins (IDPs) are sensitive to small energetic-entropic differences between intramolecular and protein−solvent interactions
This can be observed in studies of denatured states of folded proteins.[14−16] It should, be possible to tune the dimensions of natural IDPs through small perturbations of basic thermodynamic factors including backbone conformational entropy, hydrophobicity, and charge−charge interactions, thatstabilize pockets of structure
M utational perturbation of protein structures reveals position-specific and context-dependent information on protein structure network, folding, function, allostery, and epistasis.[1−4] A majority of studies have been performed on ordered proteins with a compact hydrophobic core and a welldefined three-dimensional structure.[5−8] elementary considerations of the intraprotein interaction or contact network highlight that mutations should modulate the folded versus unfolded state equilibrium and tune the relative population of intermediate and excited states and the overall dimensions of the native ensemble.[4,9]
Summary
Sneha Munshi, Divya Rajendran, Samyuktha Ramesh, Sandhyaa Subramanian, Kabita Bhattacharjee, Meagha Ramana Kumar, and Athi N. Naganathan* Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India
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