Importance of Hydrophilic Hydration and Intramolecular Interactions in the Thermodynamics of Helix–Coil Transition and Helix–Helix Assembly in a Deca-Alanine Peptide

Abstract

For a model deca-alanine peptide the cavity (ideal hydrophobic) contribution to hydration favors the helix state over extended states and the paired helix bundle in the assembly of two helices. The energetic contributions of attractive protein–solvent interactions are separated into quasi-chemical components consisting of a short-range part arising from interactions with solvent in the first hydration shell and the remaining long-range part that is well described by a Gaussian. In the helix–coil transition, short-range attractive protein–solvent interactions outweigh hydrophobic hydration and favor the extended coil states. Analysis of enthalpic effects shows that it is the favorable hydration of the peptide backbone that favors the unfolded state. Protein intramolecular interactions favor the helix state and are decisive in favoring folding. In the pairing of two helices, the cavity contribution outweighs the short-range attractive protein–water interactions. However, long-range, protein–solvent attractive interactions can either enhance or reverse this trend depending on the mutual orientation of the helices. In helix–helix assembly, change in enthalpy arising from change in attractive protein–solvent interactions favors disassembly. In helix pairing as well, favorable protein intramolecular interactions are found to be as important as hydration effects. Overall, hydrophilic protein–solvent interactions and protein intramolecular interactions are found to play a significant role in the thermodynamics of folding and assembly in the system studied.

Communication: Role of explicit water models in the helix folding/unfolding processes

“…Our study in agreement with previous results, 17,22,[32][33][34] highlights the role that all-atom PFFs and especially WMs play in determining the dynamics of such systems.…”

“…However, given the continuous strive at improving the all-atom empirical potentials we must consider them relevant. Water models are known to exert some influence on the disordered state distributions, 20,[32][33][34]58 and our results confirm this. From the data reported in Fig.…”

Intramolecular Interactions Overcome Hydration to Drive the Collapse Transition of Gly15

“…13,14 This approach makes possible the facile calculation of free energies of hydration of polypeptides and proteins in all-atom simulations, 14–17 and most importantly for this study, we obtain a direct quantification of the hydrophilic and hydrophobic contributions to hydration. 16,17 We complement these studies with an evaluation of the excess enthalpy and entropy of hydration as well.…”

Predicting unfolding thermodynamics and stable intermediates for alanine-rich helical peptides with the aid of coarse-grained molecular simulation

“…Stronger hydrophobic interactions of exposed side chains in the folded or unfolded states are expected to lead to stronger polypeptide self-association, which may be unavoidable at finite concentrations needed for experimental measurements of unfolding. The latter typically leads to lower T m values [6,46,49]. Finally, the electrostatic contributions (Figure 4D) do not show any correlation with observed T m values, and the energy values are two orders of magnitude smaller than the other two contributions.…”

“…On the other hand, proper protein self-assembly is responsible for much of the physiological functions of proteins in vivo . [1,4–6]…”