Short-Range Backbone Dihedral Rotations Modulate Internal Friction in Intrinsically Disordered Proteins

Abstract

Protein folding and dynamics are governed by an intricate interplay of thermal and viscosity-mediated effects. The solvent viscosity contributes to the frictional drag in protein dynamics. In addition to this viscosity-dependent effect, there is also an intriguing viscosity-independent component that represents the intrinsic resistance of the polypeptide chain to changing its conformation. This solvent-independent component is termed internal friction. A longstanding question is what is the fundamental molecular origin of internal friction in highly solvated and rapidly fluctuating intrinsically disordered proteins (IDPs) devoid of any persistent intrachain interactions? Here, we present a unique case to directly demonstrate that sequence-specific backbone dihedral barriers control local internal friction in an archetypal IDP, namely, α-synuclein. We performed site-directed fluorescence depolarization kinetics using picosecond time-resolved fluorescence anisotropy measurements to directly observe the directional decorrelation arising due to short-range backbone torsional fluctuations in the dihedral space. A linear viscosity-dependent model of the dihedral relaxation time yielded a finite zero-viscosity intercept that corresponds to internal friction. Our site-specific dynamic readouts were able to detect localized sequence-specific frictional components that are otherwise skewed in viscosity-dependent long-range chain fluctuations. Our results revealed the presence of low internal friction in nonproline sequence segments. In contrast, a proline introduces torsional stiffness in the segment exhibiting high internal friction that can be compensated by a conformationally flexible glycine. Such an intriguing interplay of local dihedral dynamics can modulate sequence-dependent internal friction in a wide range of IDPs involved in a myriad of important events including folding, binding, assembly, and phase transitions.

Ultraslow Biological Water-Like Dynamics in Waterless Liquid Protein

“…28 The correlation between hydration times and amyloid transition 29 has been used to decipher the molecular origin of the dynamic heterogeneity of water in different regions of an intrinsically disordered protein. 30 It has been useful in distinguishing between hard and soft sphere interactions for proteins in a crowded environment. 31 Solvation dynamics, time-resolved fluorescence depolarization, 32 and fluorescence correlation spectroscopy (FCS) 33−35 studied in conjunction can yield holistic pictures of structure and dynamics of proteins, especially in crowded environments, as demonstrated for human serum albumin (HSA), labeled covalently with a solvation probe, 7-(diethylamino)-3-(4-maleimidophenyl)-4methylcoumarin (CPM), in its conjugates with a pluronic triblock copolymer.…”

“…The enigmatic slow dynamics of biological water is one such phenomenon that continues to fascinate the scientific community. − Ultrafast solvation dynamics of bulk water , is known to slow considerably in microheterogeneous media. − Such hydration dynamics has been found to drive side-chain motion of proteins in picosecond time scales, and this has been proposed to be an important factor in determining the structure and function of proteins and also in chaperone-aided protein folding . The correlation between hydration times and amyloid transition has been used to decipher the molecular origin of the dynamic heterogeneity of water in different regions of an intrinsically disordered protein . It has been useful in distinguishing between hard and soft sphere interactions for proteins in a crowded environment .…”

Molecular Origin of Internal Friction in Intrinsically Disordered Proteins

“…Chem. Soc.202214417391747 . This work unmasked the molecular origin of internal friction in intrinsically disordered proteins.…”

“…Therefore, the corollary of eq defining the equivalency between Kramers’ theory and Stokes’ law does hold for proteins only under the assumption where we conjecture that frictional parameter γ is directly proportional to solvent viscosity parameter η and it does not consider the influence of any other energy dissipation apart from the external solvent drag. In a practical scenario, relaxation processes in proteins often exhibit unusually slower dynamics that are primarily governed by two types of energy dissipation mechanisms: (a) external energy dissipation originating from solvent friction and (b) internal energy dissipation within the inner coordinates of the protein that does not influence the conformational behavior along the reaction or conformational change coordinate. , This additional contribution from internal energy dissipative force operative within the polypeptide chain is termed “internal friction”. ,,, …”

Variation of Structural and Dynamical Flexibility of Myelin Basic Protein in Response to Guanidinium Chloride

“…IDPs are exceptionally rich in polar and charged residues in comparison to globular proteins [3,4], which results in a plethora of structural states that are separated by low energy barriers [5]. These characteristics allow IDPs to dynamically sample a huge conformational ensemble by means of large-scale correlated motions of the protein chain [6,7] that are connected to backbone torsional rotations occurring on short length ranges [8,9]. Concurrently, IDPs are highly susceptible in their structural and dynamical response to external perturbations, e.g., variation of ionic strength [10] or solution osmolarity [11], and this constitutes an inherent mechanism of IDPs to respond to local variations of the intracellular medium [12].…”