GB1 hairpin kinetics: capturing the folding pathway with molecular dynamics, replica exchange and optimal dimensionality reduction

Krzysztof Kuczera, Robert Szoszkiewicz, Christopher L. Shaffer, Gouri S. Jas

Research output: Contribution to journalArticlepeer-review


We have performed molecular dynamics (MD) and replica-exchange (REMD) simulations of folding of the GB1 hairpin peptide in aqueous solution. REMD results were consistent with a cooperative zipper folding model. 120 (Formula presented.) MD trajectories at 320 K yielded relaxation times of 1.8 (Formula presented.) and 100 ns, with the slower assigned to global folding. The MD folding/unfolding transitions also followed the cooperative zipper model, specifying nucleation at the central turn followed by consecutive hydrogen bond formation. Formation of hydrogen bonds and hydrophobic contacts were highly correlated. Coarse-grained kinetic models constructed with the Optimal Dimensionality Reduction (ODR) approach found a folding time of 3.3 (Formula presented.) and unfolding time of 4.0 (Formula presented.) Additionally, relaxation times in the 130–170 ns range could be assigned to formation of the transition state and off-path intermediates. The unfolded state was the most highly populated and, significantly, most heterogenous, assembling the largest number of microstates, primarily composed of extended and turn structures. The folded state was also heterogenous, but a to a lesser degree, involving the fully folded and partially folded in-register hairpins at early stages of the zipper pathway. The transition state corresponded to the nucleated hairpin, with central turn and first beta-sheet hydrogen bond, while the off-path intermediates were off-register partial hairpins. Our simulation results were in excellent agreement with experimental data on folded fraction, relaxation time and folding mechanism. The new findings from this work suggest a highly cooperative zipper folding mechanism, nascent hairpin transition state and ∼100 ns relaxation related to intermediate formation. Communicated by Ramaswamy H. Sarma.

Original languageEnglish (US)
Pages (from-to)11671-11680
Number of pages10
JournalJournal of Biomolecular Structure and Dynamics
Issue number21
StatePublished - 2023


  • GB1 hairpin peptide
  • folding pathways
  • kinetic modeling
  • molecular dynamics
  • replica-exchange molecular dynamics

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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