Sucrose prevents protein fibrillation through compaction of the tertiary structure but hardly affects the secondary structure

Abstract

Amyloid fibers, implicated in a wide range of diseases, are formed when proteins misfold and stick together in long rope-like structures. As a natural mechanism, osmolytes can be used to modulate protein aggregation pathways with no interference with other cellular functions. The osmolyte sucrose delays fibrillation of the ribosomal protein S6 leading to softer and less shaped-defined fibrils. The molecular mechanism used by sucrose to delay S6 fibrillation was studied based on the two-state unfolding kinetics of the secondary and tertiary structures. It was concluded that the delay in S6 fibrillation results from stabilization and compaction of the slightly expanded tertiary native structure formed under fibrillation conditions. Interestingly, this compaction extends to almost all S6 tertiary structure but hardly affects its secondary structure. The part of the S6 tertiary structure that suffered more compaction by sucrose is known to be the first part to unfold, indicating that the native S6 has entered the unfolding pathway under fibrillation conditions.

Alginate-based hydrogels as drug delivery vehicles in cancer treatment and their applications in wound dressing and 3D bioprinting

“…Alginate gelation is done under the mild conditions using non-toxic reactants. It has capability to form the gels by substitution of the sodium ions from the guluronic acids with the divalent cations such as Ca + 2 which crosslink the polymer chains through the "egg-box" model [17][18][19] or by decreasing the pH value below the pKa of ALG monomers by using the lactones like dglucono--lactone [11]. During the studies, it was determined that various factors such as composition, molecular weight as well as the gel-forming kinetics and the cation have a significant influence in several critical properties that involved in porosity, swelling behavior, constancy, biodegradability, gel strength, and the gel's immunological characteristics and biocompatibility [9].…”

Influence of Hyperglycemic Conditions on Self-Association of the Alzheimer’s Amyloid β (Aβ1–42) Peptide

“…Such behavior qualitatively agrees with experimental and computational findings that sugars, which function as osmolytes within cells, hamper the aggregation of amyloidogenic peptides or globular proteins. 36 , 98 − 101 We point out that previous reports of Aβ dimerization have ignored the contributions arising due to loss in configurational entropy. 93 , 102 We estimated the cumulative configurational entropy of the protein backbone atoms of the Aβ peptides for the PW-D and PG-D systems, calculated for the initial 10 ns of the dimerizing trajectories when the proteins exist as individual units as well as for the last 10 ns when the proteins have dimerized, using Schlitter’s method, 103 as described in the Supporting Information (SI) .…”

Stability of Protein Formulations at Subzero Temperatures by Isochoric Cooling

“…30 Sucrose that stabilizes and compacts mostly the tertiary structure, hardly affecting the secondary structure, also delays amyloid aggregation namely the 3Hmut Wil involved in amyloid light-chain amyloidosis. 31,32 The relevance of unfolding thermodynamics to predict kinetics of irreversible pathways such as protein aggregation has been well documented. 3,33 In summary, osmolytes increase the protein half-life not by slowdown of the intrinsic kinetics of irreversible pathways that lead to deactivation, such as aggregation, but because they shift the unfolding equilibrium toward the native structure.…”