First Principles Prediction of Protein Folding Rates:

A Quantitative Mechanism of Early Protein Folding

Derek A. Debe and William A. Goddard III

Materials and Process Simulation Center (MSC), Dept. of Chemistry and Chemical Engineering, California Institute of Technology

Experimental studies have demonstrated that many small, single-domain proteins fold via simple two-state kinetics. We present a first principles approach, the Native Topology Probability (NTP) method, for predicting the folding rates of specific proteins. Our approach assumes a nucleation-condensation mechanism of folding, where the rate-limiting step is a random, diffusive search for the native tertiary topology. We have applied the NTP method to the 21 topologically distinct small proteins for which two-state rate data is available. For the 18 beta-sheet and mixed alpha-beta native proteins, we predict folding rates within an average factor of 4, even though the experimental rates vary by a factor of ~4´ 104. Our successful rate predictions strongly suggest that small, single domain proteins can fold by a two-state folding mechanism consisting of:

  1. random, diffusive sampling to find the native topology, followed by
  2. non-random, local conformational changes within the native topology to settle into the unique native state.

According to such a mechanism, many different pathways can result in a correctly folded protein. Hence, such a mechanism supports the use of computationally tractable ab-initio, threading and rational protein design procedures that ignore folding pathway considerations while assessing the compatibility between sequence and tertiary structure.