Proline and Water Stabilization of a Universal Two-Step Folding Mechanism for β-Turn Formation in Solution

Abstract

The atomic scale process by which proteins fold into their functional forms in aqueous solutions is still not well understood. While there is clearly an interplay between the sequence of the protein and the surrounding water solvent that leads to highly specific and reproducible folding in nature, there is still an ongoing debate concerning how water molecules aid in driving the folding process. By using a combination of techniques that provide information at the atomic level-neutron and X-ray diffraction and computer simulations-the mechanism of folding in a series of peptides that only vary with respect to the central side-chain residue has been determined. Specifically, β-turn formation for the KGXGK peptide (where X = P, G, S or L) occurs via a two-step water-driven attraction between specific sites on the peptide backbone. This proposed mechanism suggests that the site-specific hydration of the backbone facilitates the initial stages of protein folding and that this hydration interaction in combination with the presence of proline in the i + 1 position helps to stabilize the folded and intermediate folding state of the peptide in solution, leading to a greater propensity for PG containing sequences to occur in β-turns in proteins.

Electronic circular dichroism and nuclear magnetic resonance studies of peptides derived from the FKBP52‐interacting β‐turn of the hERα ligand‐binding domain

“…As a reference, we recorded the ECD spectra of the noncyclic analogue (Peptide 17 : Ac‐CR t LPGFC‐NH 2 ) under the same experimental conditions. Heating of this peptide (Figure C) was accompanied by a change in the ECD spectrum and an isodichroic point at ∼ 220 nm, revealing a mixture of random coil and turn conformations similar to what was observed with the parent peptide 6 , which could, in water, be attributed to open/medium and closed conformational states, as recently proposed …”

Aggregated Amphiphilic Antimicrobial Peptides Embedded in Bacterial Membranes

“…MD simulations were used to explore how AMPs interact with model bacterial membranes and such studies have offered useful insights into the different molecular structures of AMPs. , All-atom MD (AA MD) simulations can take into account all pair-wise atom–atom interactions, but these studies are often limited to small box sizes with very limited numbers of AMPs and lipids, and relatively short timescales, for example, within 10–100 ns. In contrast, a large number of CG lipid models and force fields (FFs) have been developed to work on large sample boxes incorporating large numbers of molecules.…”

Role of Water in Sucrose, Lactose, and Sucralose Taste: The Sweeter, The Wetter?

“…In recent years, this combination has been successfully employed to investigate the ability of small molecules to form hydrophilic/phobic interactions in solution. 23−27…”

“…To tackle this issue, we have employed a combination of neutron diffraction with isotopic substitution and a simulation method known as empirical potential structure refinement (EPSR) developed in the disordered materials group at the ISIS Neutron and Muon Source. In recent years, this combination has been successfully employed to investigate the ability of small molecules to form hydrophilic/phobic interactions in solution. − …”