Entropic Contributions to Protein Stability

Abstract

Thermodynamic stability is an important property of proteins that is linked to many of the trade‐offs that characterize a protein molecule and therefore its function. Designing a protein with a desired stability is a complicated task given the intrinsic trade‐off between enthalpy and entropy which applies for both the folded and unfolded states. Traditionally, protein stability is manipulated by point mutations which regulate the folded state enthalpy. In some cases, the entropy of the unfolded state has also been manipulated by means that drastically restrict its conformational dynamics such as engineering disulfide bonds. In this mini‐review, we survey various approaches to modify protein stability by manipulating the entropy of either the unfolded or the folded states. We show that point mutations that involve elimination of long‐range contacts may have a greater destabilization effect than mutations that eliminate shorter‐range contacts. Protein conjugation can also affect the entropy of the unfolded state and thus the overall stability. In addition, we show that entropy can contribute to shape the folded state and yield greater protein stabilization. Hence, we argue that the entropy component can be practically manipulated both in the folded and unfolded state to modify protein stability.

Exploring Glycan Binding Specificity of Odorranalectin by Alanine Scanning Library

“…Thus, glycine flexible nature allows conformational changes to occur in OL for effective binding [32] . Our results show that Ser 3 , Pro 4 , and Val 13 are not essential for binding, and we hypothesize that the structural rearrangements brought by Ala substitution either increase the binding by stabilization (rigidification) of the native conformation of OL (folded state) and/or by destabilization of the unfolded state by decreasing its entropy [33–35] …”

“…[32] Our results show that Ser 3 , Pro 4 , and Val 13 are not essential for binding, and we hypothesize that the structural rearrangements brought by Ala substitution either increase the binding by stabilization (rigidification) of the native conformation of OL (folded state) and/or by destabilization of the unfolded state by decreasing its entropy. [33][34][35] Overall, binding assay with BSA-conjugated monosaccharides provided better insights into key amino acids positions involved in binding of OL to monosaccharides. Ala substitutions that disrupt binding indicate that residues such as Lys 5 , Phe 7 , Arg 8 , Leu 14 , and Thr 17 directly interact with monosaccharides.…”

Antifreeze Proteins: A Tale of Evolution From Origin to Energy Applications

“…The dynamics of the protein conformation is subject to change by the intrinsically free energy between entropy and enthalpy for both folded and unfolded configurations. However, studies suggested that the stability of a folded protein is significant due to its overall residual entropy (Bigman and Levy, 2020). Parameters such as temperature and pH change the protein stability and cause denaturation as a result of destabilizing bonds and altering charges.…”

Double mutant of chymotrypsin inhibitor 2 stabilized through increased conformational entropy

“…where 𝜏 -+ = 𝜏 1 -+ + 𝜏 " -+ and with 𝑆 & , 𝜏 " as fitting parameters. C(t) was further multiplied by 𝜉 = (1.02/1.041) 6 , to include the effect of vibrational averaging on dipolar couplings. 53 An isotropic diffusion model was applied using the experimentally derived global rotational diffusion times 𝜏 1 (see NMR methods).…”

“…If the dynamics of the native state is increased without significantly affecting the intermolecular interactions it will lead to a more stable protein. 5,6 Typically, however, the increased dynamics is counteracted by fewer stabilizing interactions through entropy-enthalpy compensation in the more dynamic molecule. 7,8 In some cases evolution has circumvented this problem.…”