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The Flory isolated-pair hypothesis is not valid for polypeptide chains: implications for protein folding.
R V Pappu1, R Srinivasan, G D Rose
1Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-2185, USA.
Summary
Short polyalanyl chains exhibit steric effects beyond nearest neighbors, challenging the isolated-pair hypothesis. This finding reduces the calculated entropy cost for adopting specific protein conformations.
Area of Science:
- Computational chemistry
- Biophysics
- Protein folding
Background:
- Flory's isolated-pair hypothesis simplifies protein folding by assuming steric independence of phi,psi pairs.
- This hypothesis is fundamental to helix-coil theories and understanding protein conformational landscapes.
Purpose of the Study:
- To reevaluate Flory's isolated-pair hypothesis using an all-atom representation of short polyalanyl chains.
- To investigate the extent of steric effects in intrachain interactions and their impact on conformational space.
Main Methods:
- Exhaustive enumeration of sterically allowed conformations for short polyalanyl chains.
- Inclusion of intrachain interactions and a single adjustable parameter for backbone energy (e.g., peptide hydrogen bond).
Main Results:
- Steric effects were found to extend beyond nearest-chain neighbors, contradicting the isolated-pair hypothesis.
- The accessible conformational space was significantly restricted by these non-local steric interactions.
- The calculated entropy cost for adopting specific conformations was substantially lower than previously estimated.
Conclusions:
- Flory's isolated-pair hypothesis is an oversimplification, as steric effects are more pervasive.
- A more accurate understanding of protein folding and conformational entropy requires considering these extended steric interactions.
- The reduced entropy price has significant implications for predicting protein stability and folding pathways.