Peptide loop-closure kinetics from microsecond molecular dynamics simulations in explicit solvent.

Area of Science:

• Biophysics
• Computational Chemistry
• Protein Folding Dynamics

Background:

• Experimental measurements of peptide end-to-end contact formation rates were recently performed using tryptophan triplet quenching.
• Understanding peptide loop-closure kinetics is crucial for elucidating early events in protein folding.

Purpose of the Study:

• To investigate loop-closure kinetics for two peptides of varying lengths using all-atom explicit-solvent molecular dynamics simulations.
• To compare simulation results directly with experimental data and analyze peptide dynamics in the unfolded state.

Main Methods:

• Conducted multiple all-atom explicit-solvent molecular dynamics simulations for Cys-(Ala-Gly-Gln)n-Trp peptides (n=1, 2) with different initial conditions and force fields (AMBER, CHARMM).
• Collected extensive simulation data (1.0-0.8 microseconds for pentapeptide, ~0.5 microseconds each for octapeptide) for atomic-resolution analysis.
• Analyzed peptide dynamics in the unfolded state to probe early protein folding events.

Main Results:

• Calculated tryptophan triplet state lifetimes were in the range of 50-100 ns, consistent with experimental findings.
• Observed significantly faster end-to-end contact formation rates, with characteristic times under 10 ns.
• Demonstrated similar contact formation rates between the AMBER and CHARMM force fields, despite variations in peptide conformation ensembles.

Conclusions:

• Molecular dynamics simulations provide valuable atomic-resolution insights into early protein folding dynamics.
• Peptide end-to-end contact formation is a rapid process, occurring on timescales faster than previously suggested by some interpretations of experimental data.
• The choice of force field (AMBER vs. CHARMM) has a minimal impact on the calculated end-to-end contact formation rates for these peptides.