Structure-function relationship of proteins has been rethought over the past decades to account for conformational variation and its functional role. Studying conformational variation of proteins requires ensemble descriptions and capability of probing coupled dynamics between conformational fluctuations and folding/bindings events, which create challenges for molecular spectroscopy. Computational advances have been made to help interpret conformational structure and dynamics, including Markov state models (MSMs) to identify conformational states and corresponding inter-conversion kinetics, and spectroscopic maps which provide direct route to compute infrared (IR) spectra from protein structures.<br/>In this talk, we present a joint experimental and computational approach to uncovering conformational heterogeneity of insulin monomer and dimer through site-specific isotope-edited IR spectroscopy, MSMs, and computational amide I spectroscopy. With the help of atomistic simulations, we observe elements of disorder in the insulin monomer ensemble, which are further supported by experimental isotope-edited IR spectroscopy and hydrogen-exchange protection factors. Using a similar approach, we also identify a previously uncharacterized twisted dimeric state that is consistent with experimental isotope-edited spectroscopy. Combining computational models with experimental isotope-edited IR spectroscopy provides an effective way to investigate conformational variation and dynamics in protein.

Conformational variation of insulin studied by isotope-edited infrared spectroscopy, Markov state models, and computational spectroscopy

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ACS Fall 2022

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