Sensitivity of local hydration behaviour and conformational preferences of peptides to choice of water model

Abstract

Hydration of the 16-residue β-hairpin fragment of the protein in the folded and unfolded ensembles is studied with mTIP3P and TIP4P solvent models using the CHARMM22 protein force-field. mTIP3P is a three-site water model which is used for parameterization of the CHARMM force-field and is known to exhibit liquid-state anomalies of water at temperatures about 80 K lower than the experimental temperature. TIP4P is a four-site water model which gives a better description of the experimental phase diagram and liquid-state anomalies of water. At a temperature of 250 K, where the folded ensemble of the peptide is stable and the unfolded ensemble is metastable, secondary structure metrics are much more sensitive to the choice of solvent model in the unfolded, rather than folded, ensemble. In particular, mean values as well as variation in the positional root mean square displacements (RMSD) and configurational entropy are greater in mTIP3P compared to the TIP4P solvent. The peptide structure is relatively more compact in the TIP4P solvent, which supports unfolded as well as hydrophobic core states. In terms of average local order and binding energy of the water surrounding the peptide, strong deviations from bulk behaviour are restricted to the first hydration shell and differences between the folded and unfolded ensembles in the two solvents are small. The strong coupling between the solvent and the peptide is demonstrated, however, by the dependence of the unfolding temperature on the water model (400 K in mTIP3P and 465 K in TIP4P) and the qualitatively different temperature dependence of the hydration layer occupancy signalling the unfolding transition in the two solvents. A residue-wise decomposition of different contributions to the configurational energy indicates that the TIP4P solvent shows far greater variation in the interaction with charged sidegroups of amino acid residues than the mTIP3P solvent. The implications of sequence-dependent sensitivity of peptide secondary structures to the choice of water models for simulating folding-unfolding equilibria and free energy landscapes are discussed.

Origin of the blueshift of water molecules at interfaces of hydrophilic cyclic compounds

“…Furthermore, we demonstrated the relationship between the blueshift and the perturbation of the tetrahedral structure in water molecules at the hydrophilic interface. This perturbation of water molecules in the first hydration shell has previously been observed for many biological materials, for example, DNA ( 21 ), small peptides ( 22 – 24 ), and various proteins ( 20 ). Therefore, it can be extrapolated that the observed blueshift occurs not only at monosaccharide interfaces but also at the other materials and that these properties are essential to understanding the complex nature of many water-material interfaces.…”

Influence of Ionic Strength on Hydrophobic Interactions in Water: Dependence on Solute Size and Shape

“… 73 − 75 Our results showed that the hydration properties of water were sensitive to the choice of water model. The choice of solvent model has a greater effect on the unfolded state than on the folded state of peptides, 76 which is crucial in such studies. Experimental data could be helpful in deciding which model is more reliable for hydrophobic interactions; however, such data are currently unavailable.…”

Revisiting the conundrum of trehalose stabilization

“…The system is labelled den1. The second approach involves carrying out simulations of protein at 500 K and randomly picking one of the unfolded conformations (the unfolded conformation is defined as the one which contains less than or nearly 50% of the native contacts as completely unfolded conformations are difficult to obtain for larger proteins as reported earlier 40 ) and then quenching it rapidly to 300 K at the rate of 1 K ps À1 [in order to obtain molten globule state 41 ], followed by NPT equilibration of 100 ps and finally 50 ns NPT production run. Three different conformations were chosen between 30 and 50 ns (considering first 20 ns to be an equilibration phase).…”