The contribution of electrostatics to hydrogen exchange in the unfolded protein state

Rupashree Dass; Enrico Corlianò; Frans A.A. Mulder

doi:10.1016/j.bpj.2021.08.003

The contribution of electrostatics to hydrogen exchange in the unfolded protein state

Rupashree Dass, Enrico Corlianò, Frans A.A. Mulder^*

^*Corresponding author for this work

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Abstract

Although electrostatics have long been recognized to play an important role in hydrogen exchange (HX) with solvent, the quantitative assessment of its magnitude in the unfolded state has hitherto been lacking. This limits the utility of HX as a quantitative method to study protein stability, folding, and dynamics. Using the intrinsically disordered human protein α-synuclein as a proxy for the unfolded state, we show that a hybrid mean-field approach can effectively compute the electrostatic potential at all backbone amide positions along the chain. From the electrochemical potential, a fourfold reduction in hydroxide concentration near the protein backbone is predicted for the C-terminal domain, a prognosis that is in direct agreement with experimentally derived protection factors from NMR spectroscopy. Thus, impeded HX for the C-terminal region of α-synuclein is not the result of intramolecular hydrogen bonding and/or structure formation.

Original language	English
Journal	Biophysical Journal
Volume	120
Issue	18
Pages (from-to)	4107-4114
Number of pages	8
ISSN	0006-3495
DOIs	https://doi.org/10.1016/j.bpj.2021.08.003
Publication status	Published - Sept 2021

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title = "The contribution of electrostatics to hydrogen exchange in the unfolded protein state",

abstract = "Although electrostatics have long been recognized to play an important role in hydrogen exchange (HX) with solvent, the quantitative assessment of its magnitude in the unfolded state has hitherto been lacking. This limits the utility of HX as a quantitative method to study protein stability, folding, and dynamics. Using the intrinsically disordered human protein α-synuclein as a proxy for the unfolded state, we show that a hybrid mean-field approach can effectively compute the electrostatic potential at all backbone amide positions along the chain. From the electrochemical potential, a fourfold reduction in hydroxide concentration near the protein backbone is predicted for the C-terminal domain, a prognosis that is in direct agreement with experimentally derived protection factors from NMR spectroscopy. Thus, impeded HX for the C-terminal region of α-synuclein is not the result of intramolecular hydrogen bonding and/or structure formation.",

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AU - Corlianò, Enrico

AU - Mulder, Frans A.A.

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AB - Although electrostatics have long been recognized to play an important role in hydrogen exchange (HX) with solvent, the quantitative assessment of its magnitude in the unfolded state has hitherto been lacking. This limits the utility of HX as a quantitative method to study protein stability, folding, and dynamics. Using the intrinsically disordered human protein α-synuclein as a proxy for the unfolded state, we show that a hybrid mean-field approach can effectively compute the electrostatic potential at all backbone amide positions along the chain. From the electrochemical potential, a fourfold reduction in hydroxide concentration near the protein backbone is predicted for the C-terminal domain, a prognosis that is in direct agreement with experimentally derived protection factors from NMR spectroscopy. Thus, impeded HX for the C-terminal region of α-synuclein is not the result of intramolecular hydrogen bonding and/or structure formation.

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The contribution of electrostatics to hydrogen exchange in the unfolded protein state

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