How fast fast-folding proteins fold in silico

Area of Science:

• Computational Biology
• Biophysics
• Protein Dynamics

Background:

• Previous microcanonical simulations showed slow protein folding compared to experiments.
• Discrepancies in folding times (4-10x longer) limited in silico accuracy for fast-folding proteins like CLN025 and Trp-cage.

Purpose of the Study:

• To achieve autonomous protein folding in silico with folding times comparable to experimental values.
• To improve the accuracy of molecular dynamics simulations for fast-folding proteins.

Main Methods:

• Utilized isobaric-isothermal molecular dynamics simulations.
• Simulated autonomous folding of fast-folding proteins CLN025 and Trp-cage.

Main Results:

• Achieved autonomous folding of CLN025 and Trp-cage in silico.
• Simulated folding times agreed with experimental values within factors of 0.69-1.75 across temperatures.
• Demonstrated that in silico folding times now match experimental rates for these proteins.

Conclusions:

• Isobaric-isothermal simulations enable accurate prediction of fast protein folding dynamics.
• The accuracy of folding simulations now overlaps with experimental accuracy for fast-folding proteins.
• Opens avenues for AI-driven prediction of protein conformational ensembles and dynamics for biological function.