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Folding, misfolding and aggregation of proteins and peptides: a molecular dynamics study
Full text linkInvestigating the accessibility of the closed domain conformation of citrate synthase using essential dynamics sampling
No full textCommon Folding Mechanism of a beta-Hairpin Peptide via Non-native Turn Formation Revealed by Unbiased Molecular Dynamics Simulations
No full textThe folding of a 15-residue beta-hairpin peptide (Peptide 1) is characterized using multiple unbiased,
atomistic molecular dynamics (MD) simulations. Fifteen independent MD trajectories, each 2.5 μs-long for
a total of 37.5 μs, are performed of the peptide in explicit solvent, at room temperature, and without the
use of enhanced sampling techniques. The computed folding time of 1-1.5 μs obtained from the simulations
is in good agreement with experiment [Xu, Y.; et al. J. Am. Chem. Soc. 2003, 125, 15388-15394]. A
common folding mechanism is observed, in which the turn is always found to be the major determinant in
initiating the folding process, followed by cooperative formation of the interstrand hydrogen bonds and the
side-chain packing. Furthermore, direct transition to the folded state from fully unstructured conformations
does not take place. Instead, the peptide is always observed to form partially structured conformations
involving a non-native (ESYI) turn from which the native (NPDG) turn forms, triggering the folding to the
beta-hairpin
Theoretical characterization of alpha-helix and beta-hairpin folding kinetics RID B-7035-2008
No full text
Structured pathway across the transition state for peptide folding revealed by molecular dynamics simulations.
No full textSmall globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide chain reaches, and leaves, the TS by completely random fluctuations, or whether there is a directed, stepwise process. Here, the folding TS of a 15-residue β-hairpin peptide, Peptide 1, is characterized using independent 2.5 μs-long unbiased atomistic molecular dynamics (MD) simulations (a total of 15 μs). The trajectories were started from fully unfolded structures. Multiple (spontaneous) folding events to the NMR-derived conformation are observed, allowing both structural and dynamical characterization of the folding TS. A common loop-like topology is observed in all the TS structures with native end-to-end and turn contacts, while the central segments of the strands are not in contact. Non-native sidechain contacts are present in the TS between the only tryptophan (W11) and the turn region (P7-G9). Prior to the TS the turn is found to be already locked by the W11 sidechain, while the ends are apart. Once the ends have also come into contact, the TS is reached. Finally, along the reactive folding paths the cooperative loss of the W11 non-native contacts and the formation of the central inter-strand native contacts lead to the peptide rapidly proceeding from the TS to the native state. The present results indicate a directed stepwise process to folding the peptide
High density water clusters observed at high concentrations of the macromolecular crowder PEG400
No full textWhat happens to water in crowded environments? A detailed understanding of how water is affected by the presence of a crowding agent is still lacking. In the present work, we focus on macromolecular crowding. In particular, we study aqueous solutions of a macromolecular crowder with many industrial applications, namely, poly-(ethylene) glycol with a mass weight of 400 g/mol (PEG400), at compositions ranging from infinite dilution to polymer weight fractions of 0.95 by means of molecular dynamics simulations and 1H DOSY-NMR experiments. Our data show that water density is severely affected by the presence of macromolecular chains at all concentrations, and is, on average, always higher than the bulk water density as a result of the superimposition of the hydration shells of the polymer chains. Moreover, the combined computational-experimental approach concurs well with the following scenario: water still forms clusters even within the solutions at the highest concentration, rather than saturating all available hydrophilic sites of the polymeric chains, indicating a clear predilection for water-water interactions
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