Influence of Aqueous Arginine Solution on Regulating Conformational Stability and Hydration Properties of the Secondary Structural Segments of a Protein at Elevated Temperatures: A Molecular Dynamics Study

Abstract

The effects of aqueous arginine solution on the conformational stability of the secondary structural segments of a globular protein, ubiquitin, and the structure and dynamics of the surrounding water and arginine were examined by performing atomistic molecular dynamics (MD) simulations. Attempts have been made to identify the osmolytic efficacy of arginine solution, and its influence in guiding the hydration properties of the protein at an elevated temperature of 450 K. The similar properties of the protein in pure water at elevated temperatures were computed and compared. Replica exchange MD simulation was performed to explore the arginine solution’s sensitivity in stabilizing the protein conformations for a wide range of temperatures (300–450 K). It was observed that although all the helices and strands of the protein undergo unfolding at elevated temperature in pure water, they exhibited native-like conformational dynamics in the presence of arginine at both ambient and elevated temperatures. We find that the higher free energy barrier between the folded native and unfolded states of the protein primarily arises from the structural transformation of α-helix, relative to the strands. Our study revealed that the water structure around the secondary segments depends on the nature of amino acid compositions of the helices and strands. The reorientation of water dipoles around the helices and strands was found hindered due to the presence of arginine in the solution; such hindrance reduces the possibility of exchange of hydrogen bonds that formed between the secondary segments of protein and water (PW), and as a result, PW hydrogen bonds take longer time to relax than in pure water. On the other hand, the origin of slow relaxation of protein–arginine (PA) hydrogen bonds was identified to be due to the presence of different types of protein-bound arginine molecules, where arginine interacts with the secondary structural segments of the protein through multiple/bifurcated hydrogen bonds. These protein-bound arginine formed different kinds of bridged PA hydrogen bonds between amino acid residues of the same secondary segments or among multiple bonds and helped protein to conserve its native folded form firmly.

Conformational Features and Hydration Dynamics of Proteins in Cosolvents: A Perspective from Computational Approaches

“…However, in REMD, the standard Boltzmann weight factor can be used; hence, the method gains popularity in analyzing protein conformations in an aqueous solution, including a mixture of solvents. 6,9,15,16 Metadynamics is an another enhanced sampling method where one can reconstruct the free energy surface as a function of several degrees of freedom, commonly known as collective variables. In this method, an external history-dependent bias potential as a function of collective variables is applied where the potential can be decomposed into several Gaussian potentials within the collective variables space, and it forces the system to sample toward the unexplored configurations.…”

“…However, in REMD, the standard Boltzmann weight factor can be used; hence, the method gains popularity in analyzing protein conformations in an aqueous solution, including a mixture of solvents. 6 , 9 , 15 , 16 …”

“…For the ubiquitin protein, a remarkable change in RMSD and fraction of native contact values in pure water at 450 K was noted compared to that in arginine solution at this temperature (Figure 1). 16 The significant jump in the RMSD value of the protein in pure water at 450 K occurred near 100 ns. Further, the fraction of native contacts monitored throughout the simulation time suggested a significant breakdown of internal contacts of the protein at an elevated temperature beyond 100 ns in pure water.…”

“… Time evolution of the (a) root-mean-square deviation (RMSD) and (b) fraction of native contacts (NC) of protein ubiquitin in aqueous and in 2 M arginine solution at 300 and 450 K. The representative conformations of the protein obtained from the simulated trajectories are also shown for reference. Adapted from ref ( 16 ). Copyright 2022 American Chemical Society.…”

“…(b) Temperature-dependent average remaining fraction of native contact values of insulin monomer as obtained from the REMD simulations performed in 2 M arginine solution. (c) Apparent preferential binding coefficient as a function of the cutoff distance ( r ) between the local and bulk domains for equilibrated trajectories of ubiquitin in 2 M arginine solution at 300 and 450 K. Adapted from ref ( 16 ) (copyright 2022 American Chemical Society) and ref ( 6 ) (copyright 2020 American Chemical Society).…”