Experiments and Comprehensive Simulations of the Formation of a Helical Turn

Abstract

We consider the kinetics and thermodynamics of a helical turn formation in the peptide Ac-WAAAH-NH2. NMR measurements indicate that the peptide has significant tendency to form a structure of a helical turn, while temperature dependent CD establishes the helix fraction at different temperatures. Molecular Dynamics and Milestoning simulations agree with experimental observables and suggests an atomically detailed picture for the turn formation. Using a network representation two alternative mechanisms of folding are identified: (i) a direct cooperative mechanism from the unfolded to the folded state without intermediate formation of hydrogen bonds and (ii) an indirect mechanism with structural intermediates with two residues in a helical conformation. This picture is consistent with kinetic measurements that reveal two experimental time scales of sub nanosecond and several nanoseconds.

Computational study of peptide permeation through membrane: searching for hidden slow variables

“…If we identify these variables correctly then we could enhanced their sampling in a similar fashion to what we have done for the Z coordinate, by enhanced sampling techniques such us umbrella sampling [20], metadynamics [71], TAMD [31], TAMC [32] and Milestoning [42]. The advantage of using Milestoning in higher dimension is that the kinetic calculations are straightforward.…”

“…by replica exchange[41,42]), by reaction path calculations [43,44], or by chemical intuition[34,45]. For example, studies of peptide folding and unfolding in an explicit solvent use only the backbone dihedral angles of the peptide as the coarse variables [42,46]. In the present example we use chemical intuition to choose the variables that define the reaction space as explained in the Methods section.…”

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

“…Previous computational work based on this peptide has also provided a detailed description of the helix folding/unfolding processes. 25,26 However, a different partition of the configuration space as well as the use of earlier generation of force-fields do not allow a direct comparison with our results.…”

“…This property, combined with its small size, makes WH5 a perfect candidate to carry out a systematic study of the kinetics of conformational rearrangements. [22][23][24][25][26] Since we are interested in investigating the formation of a helical turn in the middle of the peptide chain, we a) ferruccio.palazzesi@phys.chem.ethz.ch classify the different WH5 conformations according to the arrangement of the three central alanines. Due to the fact that each one of these can adopt a coil or a helical configuration, this classification leads to 8 (2 3 ) different states.…”

Catch bond-like kinetics of helix cracking: Network analysis by molecular dynamics and Milestoning

“…Long helices are frequently found in molecular machines such as kinesin and myosin, and their stability under load is therefore of considerable biophysical interest. Prior theoretical investigations of helix unfolding were done without load and for shorter helices (5-20 amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14].…”