Abstract
To investigate the nature of hydrophobic collapse considered to be the driving force in protein folding, we have simulated aqueous solutions of two model hydrophobic solutes, methane and isobutylene. Using a novel methodology for determining contacts, we can precisely follow hydrophobic aggregation as it proceeds through three stages: dispersed, transition, and collapsed. Theoretical modeling of the cluster formation observed by simulation indicates that this aggregation is cooperative and that the simulations favor the formation of a single cluster midway through the transition stage. This defines a minimum solute hydrophobic core volume. We compare this with protein hydrophobic core volumes determined from solved crystal structures. Our analysis shows that the solute core volume roughly estimates the minimum core size required for independent hydrophobic stabilization of a protein and defines a limiting concentration of nonpolar residues that can cause hydrophobic collapse. These results suggest that the physical forces driving aggregation of hydrophobic molecules in water is indeed responsible for protein folding.
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Selected References
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- Akerström B., Björck L. A physicochemical study of protein G, a molecule with unique immunoglobulin G-binding properties. J Biol Chem. 1986 Aug 5;261(22):10240–10247. [PubMed] [Google Scholar]
- Connolly M. L. Solvent-accessible surfaces of proteins and nucleic acids. Science. 1983 Aug 19;221(4612):709–713. doi: 10.1126/science.6879170. [DOI] [PubMed] [Google Scholar]
- Dill K. A. Dominant forces in protein folding. Biochemistry. 1990 Aug 7;29(31):7133–7155. doi: 10.1021/bi00483a001. [DOI] [PubMed] [Google Scholar]
- Eliezer D., Jennings P. A., Wright P. E., Doniach S., Hodgson K. O., Tsuruta H. The radius of gyration of an apomyoglobin folding intermediate. Science. 1995 Oct 20;270(5235):487–488. doi: 10.1126/science.270.5235.487. [DOI] [PubMed] [Google Scholar]
- Finney J. L. Volume occupation, environment and accessibility in proteins. The problem of the protein surface. J Mol Biol. 1975 Aug 25;96(4):721–732. doi: 10.1016/0022-2836(75)90148-5. [DOI] [PubMed] [Google Scholar]
- Gerstein M., Tsai J., Levitt M. The volume of atoms on the protein surface: calculated from simulation, using Voronoi polyhedra. J Mol Biol. 1995 Jun 23;249(5):955–966. doi: 10.1006/jmbi.1995.0351. [DOI] [PubMed] [Google Scholar]
- Harpaz Y., Gerstein M., Chothia C. Volume changes on protein folding. Structure. 1994 Jul 15;2(7):641–649. doi: 10.1016/s0969-2126(00)00065-4. [DOI] [PubMed] [Google Scholar]
- KAUZMANN W. Some factors in the interpretation of protein denaturation. Adv Protein Chem. 1959;14:1–63. doi: 10.1016/s0065-3233(08)60608-7. [DOI] [PubMed] [Google Scholar]
- Levitt M. Molecular dynamics of native protein. I. Computer simulation of trajectories. J Mol Biol. 1983 Aug 15;168(3):595–617. doi: 10.1016/s0022-2836(83)80304-0. [DOI] [PubMed] [Google Scholar]
- Murzin A. G., Brenner S. E., Hubbard T., Chothia C. SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol. 1995 Apr 7;247(4):536–540. doi: 10.1006/jmbi.1995.0159. [DOI] [PubMed] [Google Scholar]
- Privalov P. L., Gill S. J. Stability of protein structure and hydrophobic interaction. Adv Protein Chem. 1988;39:191–234. doi: 10.1016/s0065-3233(08)60377-0. [DOI] [PubMed] [Google Scholar]
- Rank J. A., Baker D. A desolvation barrier to hydrophobic cluster formation may contribute to the rate-limiting step in protein folding. Protein Sci. 1997 Feb;6(2):347–354. doi: 10.1002/pro.5560060210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richards F. M. The interpretation of protein structures: total volume, group volume distributions and packing density. J Mol Biol. 1974 Jan 5;82(1):1–14. doi: 10.1016/0022-2836(74)90570-1. [DOI] [PubMed] [Google Scholar]
- Wolfenden R., Radzicka A. On the probability of finding a water molecule in a nonpolar cavity. Science. 1994 Aug 12;265(5174):936–937. doi: 10.1126/science.8052849. [DOI] [PubMed] [Google Scholar]