Length Dependent Folding Kinetics of Alanine-Based Helical Peptides from Optimal Dimensionality Reduction

Abstract

We present a computer simulation study of helix folding in alanine homopeptides (ALA)n of length n = 5, 8, 15, and 21 residues. Based on multi-microsecond molecular dynamics simulations at room temperature, we found helix populations and relaxation times increasing from about 6% and ~2 ns for ALA5 to about 60% and ~500 ns for ALA21, and folding free energies decreasing linearly with the increasing number of residues. The helix folding was analyzed with the Optimal Dimensionality Reduction method, yielding coarse-grained kinetic models that provided a detailed representation of the folding process. The shorter peptides, ALA5 and ALA8, tended to convert directly from coil to helix, while ALA15 and ALA21 traveled through several intermediates. Coarse-grained aggregate states representing the helix, coil, and intermediates were heterogeneous, encompassing multiple peptide conformations. The folding involved multiple pathways and interesting intermediate states were present on the folding paths, with partially formed helices, turns, and compact coils. Statistically, helix initiation was favored at both termini, and the helix was most stable in the central region. Importantly, we found the presence of underlying universal local dynamics in helical peptides with correlated transitions for neighboring hydrogen bonds. Overall, the structural and dynamical parameters extracted from the trajectories are in good agreement with experimental observables, providing microscopic insights into the complex helix folding kinetics.

Analytical Approaches for Deriving Friction Coefficients for Selected α-Helical Peptides Based Entirely on Molecular Dynamics Simulations

“…This is because low RMSD values do not encompass all well-folded structures and same values of end-to-end distances correspond to folded and unfolded species. 4 In a more comprehensive approach to characterize thermodynamic aspects of the KR1 peptide folding, the folding funnel has been generated via the 3D plots of the number of HBs versus end-to-end distance and apparent free energy of folding ΔG as a third coordinate. Figure 3 show the respective plots for the two trajectories, where ΔG is colorcoded.…”

Dissecting Multiple Pathways in the Relaxation Dynamics of Helix <==> Coil Transitions with Optimum Dimensionality Reduction

“…Coarse-grained kinetics employing ODR showed primarily a two-state process in the helix-coil transition in A5 and A8. Even in these short peptides, the 3 10 -helix population was an important finding in the folding path [86]. Hydrogen bond analysis further demonstrated a significant hydrogen bond fluctuation correlation between neighbors (Figure 5A,B).…”

“…Application of optimum dimensionality reduction (ODR) to a length-dependent helical homopeptide [ 86 ] provided an opportunity for direct microscopic examination of helix–coil transitions relative to the changes in amino acid composition. Analysis of the several microsecond long trajectories showed a gradual increase in helicity from A 5 to A 21 .…”

“…Coarse-grained kinetics employing ODR showed primarily a two-state process in the helix–coil transition in A5 and A8. Even in these short peptides, the 3 10 -helix population was an important finding in the folding path [ 86 ].…”

“…( D ) An example of a coarse-grained kinetic model with N = 3 dimensions for A21, based on N c = 34 initial clusters. ( E ) A summary of the helix, coil, and intermediate structural properties from the aggregated states in ODR models for A21 at various resolutions [ 86 ].…”