Energetics of cosolvent effect on peptide aggregation

Abstract

The cosolvent effect on the equilibrium of peptide aggregation is reviewed from the energetic perspective. It is shown that the excess chemical potential is stationary against the variation of the distribution function for the configuration of a flexible solute species and that the derivative of the excess chemical potential with respect to the cosolvent concentration is determined by the corresponding derivative of the solvation free energy averaged over the solute configurations. The effect of a cosolvent at low concentrations on a chemical equilibrium can then be addressed in terms of the difference in the solvation free energy between pure-water solvent and the mixed solvent with the cosolvent, and illustrative analyses with all-atom model are presented for the aggregation of an 11-residue peptide by employing the energy-representation method to compute the solvation free energy. The solvation becomes more favorable with addition of the urea or DMSO cosolvent, and the extent of stabilization is smaller for larger aggregate. This implies that these cosolvents inhibit the formation of an aggregate, and the roles of such interaction components as the electrostatic, van der Waals, and excluded-volume are discussed.Protein or peptide can be harmful upon formation of aggregate [1][2][3][4]. It is considered that such amyloidoses as Alzheimer's, Parkinson's, and prion diseases are caused by the amyloid aggregation, and the formation of inclusion body is an impeding factor for massive expression in the field of protein engineering. The extent of aggregate formation of a peptide is determined by the interactions among the peptides forming the aggregate and those between the peptides and the surrounding solvent. In fact, the potential function is fixed for the interactions within the peptide aggregate when the peptide species is identified, whereas it can be tuned for the interactions with the surrounding environment. 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 determined by the balance of the The cosolvent effect on peptide aggregation is addressed with all-atom molecular dynamics simulation and freeenergy calculation. It is shown from the variational principle that the stability of a flexible solute species is modulated ...

How ATP suppresses the fibrillation of amyloid peptides: analysis of the free-energy contributions

“…Note that for urea, the van der Waals interactions are also the main contribution to the stabilization of the 1-mer over the aggregate structures, whereas the electrostatic interactions have a minor effect. 40,41,44–46 This shows that ATP and urea suppress the amyloid fibril formation through similar mechanisms from the viewpoint of energy decomposition.…”

“…For the 3 M urea solution, we substituted 1770 water molecules with urea molecules as this number was also used in previous works. [40][41][42] The sum of all solvent molecules equals 30 000 for all studied systems. In order to determine the sizes of the simulation boxes, we additionally performed simulations without the solute in the isothermal-isobaric (NPT) ensemble for 1 ns.…”

“…The formation of n -mers from n 1-mers is a dynamic process and is in constant competition with the reverse process of the dissolution of n -mers back into their constituent monomers. It can be shown that the following equation is valid when the monomeric state and the n -mer aggregate state of a peptide are in equilibrium: 40–42 k B is the Boltzmann constant and T the temperature. ρ n is the concentration and μ ex n the excess chemical potential of the n -mer when the ideal part is taken to be k B T log ρ n .…”

“…The errors for the energy values were estimated through the procedure in Appendix B of Masutani et al 40 It should be noted that the 95% confidence interval is provided by multiplying a factor of 2 to eqn (B4) of Masutani et al 40 Appendix B: Derivation of eqn (3) The equilibrium between the monomeric and aggregate states will be shifted upon addition of a cosolvent due to the changes of the intermolecular interactions of the solutes and the corresponding changes of the excess chemical potentials. To examine how m ex n of aggregation state n as given by eqn (2) varies when a cosolvent of concentration c is added at constant temperature, the following expression is useful: 40,41 @m ex n @c ¼…”

“…The equilibrium between the monomeric and aggregate states will be shifted upon addition of a cosolvent due to the changes of the intermolecular interactions of the solutes and the corresponding changes of the excess chemical potentials. To examine how μ ex n of aggregation state n as given by eqn (2) varies when a cosolvent of concentration c is added at constant temperature, the following expression is useful: 40,41 This is an exact expression, and for its derivation, we have supposed that for unpolarizable forcefields, the intra-solute energy E S ( ψ n ) for a fixed structure ψ n is independent of the solvent environment. Eqn (A2) shows in particular that it is not necessary to compute the configurational entropy term.…”