Folding Dynamics of 10‐Residue β‐Hairpin Peptide Chignolin

Abstract

Short peptides that fold into beta-hairpins are ideal model systems for investigating the mechanism of protein folding because their folding process shows dynamics typical of proteins. We performed folding, unfolding, and refolding molecular dynamics simulations (total of 2.7 micros) of the 10-residue beta-hairpin peptide chignolin, which is the smallest beta-hairpin structure known to be stable in solution. Our results revealed the folding mechanism of chignolin, which comprises three steps. First, the folding begins with hydrophobic assembly. It brings the main chain together; subsequently, a nascent turn structure is formed. The second step is the conversion of the nascent turn into a tight turn structure along with interconversion of the hydrophobic packing and interstrand hydrogen bonds. Finally, the formation of the hydrogen-bond network and the complete hydrophobic core as well as the arrangement of side-chain-side-chain interactions occur at approximately the same time. This three-step mechanism appropriately interprets the folding process as involving a combination of previous inconsistent explanations of the folding mechanism of the beta-hairpin, that the first event of the folding is formation of hydrogen bonds and the second is that of the hydrophobic core, or vice versa.

Parallel cascade selection molecular dynamics (PaCS-MD) to generate conformational transition pathway

“…In conventional MD simulation, the first folding was observed at 0.4 μs starting from an extended conformation. 24 In distinct 1.6 and 1.8 μs conventional MD simulations, two folding events were observed at 450 ns and 1.2 μs in the former but no folding event was observed in the latter. 59 It was also reported that folding takes ∼50 ns in the replica exchange MD.…”

“…2(a)) in micro second order by all-atom (AA) MD simulations in explicit solvent. [23][24][25][26] As the reactant, extended structure was modeled using the AMBER leap module. 27 As the product, the final structure of 1-ns MD simulation in explicit water starting from the NMR structure (Model #1 in the PDB entry 1UAO) 22 was employed.…”

Effect of the thermostat in the molecular dynamics simulation on the folding of the model protein chignolin

“…For this reason, miniproteins such as the chignolin peptide [16] have been designed for use as folding models and have been a useful tool for folding studies involving long MD simulations [17][18][19]. Chignolin is a good folding model because it is constituted by only 10 residues (GYDPETGTWG) and because its tertiary structure folded in water is unique [16].…”

Why Are MD Simulated Protein Folding Times Wrong?

“…Using two peptides as examples we show that the deviations in the folding times can reach an order of magnitude for modest variations of the molecular model. We, therefore, conclude that the folding rate values obtained in molecular dynamics simulations have to be treated with care.Modern computational power is enough to simulate small proteins up to the times when they fold into their native conformations [1][2][3][4]. This is a remarkable achievement because phenomenological, relatively simple interatomic interactions built into the model lead to the molecular structures that essentially coincide with the crystallographically determined native conformations.…”

“…Modern computational power is enough to simulate small proteins up to the times when they fold into their native conformations [1][2][3][4]. This is a remarkable achievement because phenomenological, relatively simple interatomic interactions built into the model lead to the molecular structures that essentially coincide with the crystallographically determined native conformations.…”