Free-energy analysis of the hydration and cosolvent effects on the β-sheet aggregation through all-atom molecular dynamics simulation

Abstract

Energetics was analyzed for the aggregation of an 11-residue peptide. An all-atom molecular dynamics simulation was conducted with explicit solvent, and the energy-representation theory of solution was employed to compute the solvation free energies of the peptide and its aggregates. The aggregation in the pure-water solvent was observed to be inhibited by the solvation. The driving force of aggregate formation is the interactions among the peptide molecules, and the sum of the intra-aggregate and solvation terms per monomer is more favorable for larger aggregates. The effect of the cosolvent was then examined by focusing on the mixtures of water with urea and dimethyl sulfoxide (DMSO). It was actually shown that the derivative of the excess chemical potential of a flexible solute species with respect to the cosolvent concentration is determined exactly by the corresponding derivative of the free energy of solvation. The cosolvent effect on the equilibrium of aggregate formation can thus be addressed by comparing the solvation free energies with and without the cosolvent, and both the urea and DMSO cosolvents were found to inhibit the aggregation. The cosolvent-induced change in the solvation free energy was further decomposed into the contributions from the cosolvent and water. Their dependencies on the degree of aggregation were seen to be weak for large aggregates, and the roles of the electrostatic, van der Waals, and excluded-volume components in the solvation energetics were discussed.

Energetics of cosolvent effect on peptide aggregation

“…Let ψ denote the coordinate of the solute particle collectively and P(ψ) be the probability distribution function of ψ in the solution system of interest. μ ex is then expressed in the canonical (NVT) ensemble as [30]…”

“…It corresponds to the 68th to 78th residues of α-synuclein, which are considered as the key region to cause Parkinson's disease through aggregate formation [2,[40][41][42]. All-atom MD simulation was recently conducted to examine the roles of the intra-aggregate and aggregate-solvent interactions in the formations of the 8-mer, 16-mer, and 24-mer of NACore, and the effect of urea or dimethyl sulfoxide (DMSO) as a cosolvent was elucidated through free-energy calculations [30]. This review introduces a statistical-thermodynamic treatment for the aggregation of the peptide, with emphasis on the free energy of solvation of a peptide or its aggregate as the solute.…”

“…A common scheme for treating a peptide aggregate is thus to control the solvent environment with cosolvent [5-10], and since the cosolvent interacts with the peptide in a different manner from water, the interactions among the peptide, cosolvent, and water needs to be elucidated at the molecular level toward rational design of a cosolvent.The aggregation mechanism of peptide has been investigated both theoretically and experimentally . Molecular dynamics (MD) simulation has proven to be useful to address atomic-level processes, in particular, and the peptidepeptide and peptide-solvent interactions were analyzed to reveal the driving force of aggregate formation [12,14,16,[18][19][20][21][22][23][24]30]. In the context of statistical thermodynamics, the extent of peptide aggregation is described by the equilibrium constant of aggregation.…”

“…It is demonstrated quantitatively that urea and DMSO inhibit the aggregation since these cosolvents stabilize the monomer more strongly than the aggregates. pure-water solvent but also in more complex environments involving cosolvent or lipid membrane, that can be beyond the reach of exact free-energy methods or integral equation theories [30,81,86,[90][91][92][93][97][98][99][100][101][102]. The method of energy representation is approximate in practical applications, while it has been observed that the error from the approximation in the free-energy functional is not larger than the error from the use of force field [80,84,85].…”

“…The method of energy representation is approximate in practical applications, while it has been observed that the error from the approximation in the free-energy functional is not larger than the error from the use of force field [80,84,85]. The solvation free energies presented in this review were obtained by the energy-representation method [30].…”