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The topomer-sampling model of protein folding
D A Debe1, M J Carlson, W A Goddard
1Materials and Process Simulation Center, Beckman Institute (139-74), Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Summary
Proteins fold rapidly by first diffusively sampling "native topomers" and then ordering within the correct topomer. This two-stage process explains how proteins achieve subsecond folding times.
Area of Science:
- Protein dynamics
- Computational biology
- Biophysics
Background:
- Proteins must fold within seconds in vivo, yet possess a vast conformational space.
- Exploring all possible protein conformations is computationally intractable on biological timescales.
Purpose of the Study:
- Introduce the concept of the "native topomer" to explain rapid protein folding.
- Develop a computational method to estimate the number of distinct topomers.
- Investigate the role of topomer sampling in subsecond protein folding.
Main Methods:
- Defined native topomers as sets of similar protein structures.
- Developed a computational procedure to estimate the number of distinct topomers for a given polypeptide length.
- Calculated the diffusion time between topomers to estimate sampling rates.
Main Results:
- A 100-residue protein comprises approximately 3 x 10^7 distinct topomers.
- The estimated time to sample one topomer is approximately 3 nanoseconds.
- A 100-residue protein can find its native topomer via random sampling in approximately 100 milliseconds.
Conclusions:
- Subsecond protein folding likely involves a two-stage process: topomer diffusion and intratopomer ordering.
- Topomer diffusion allows rapid exploration of conformational space.
- Intratopomer ordering facilitates the final precise arrangement into the native state.