Hydrophobic collapse

Hydrophobic collapse is a proposed process for the production of the 3-D conformation adopted by polypeptides and other molecules in polar solvents. The theory states that the nascent polypeptide forms initial secondary structure (ɑ-helices and β-strands) creating localized regions of predominantly hydrophobic residues. The polypeptide interacts with water, thus placing thermodynamic pressures on these regions which then aggregate or "collapse" into a tertiary conformation with a hydrophobic core. Incidentally, polar residues interact favourably with water, thus the solvent-facing surface of the peptide is usually composed of predominantly hydrophilic regions.[1]

Figure 7. Illustration of the hydrophobic collapse during protein folding. In the compact fold (to the right), the hydrophobic amino acids (shown as black spheres) are in general shielded from the solvent.

Hydrophobic collapse may also reduce the affinity of conformationally flexible drugs to their protein targets by reducing the net hydrophobic contribution to binding by self association of different parts of the drug while in solution. Conversely rigid scaffolds (also called privileged structures) that resist hydrophobic collapse may enhance drug affinity.[2][3][4]

Partial hydrophobic collapse is an experimentally accepted model for the folding kinetics of many globular proteins, such as myoglobin,[5] alpha-lactalbumin,[6] barstar,[7] and staphylococcal nuclease.[8] However, because experimental evidence of early folding events is difficult to obtain, hydrophobic collapse is often studied in silico via molecular dynamics and Monte Carlo simulations of the folding process.[9][10] Globular proteins that are thought to fold by hydrophobic collapse are particularly amenable to complementary computational and experimental study using phi value analysis.[11]

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  3. ^ Rich D (1993). "Effect of Hydrophobic Collapse on Enzyme Inhibitor Interactions. Implications for the Design of Peptidomimetics.". In Testa B, Kyburz E, Fuhrer W, Giger R (eds.). Perspectives in Medicinal Chemistry: XIIth International Symposium on Medicinal Chemistry. Weinheim: VCH. pp. 15–25. ISBN 978-3-527-28486-3.
  4. ^ Rich D, Estiarte M, Hart P (2003). "Stereochemical Aspects of Drug Action I: Conformational Restriction, Steric Hindrance, and Hydrophobic Collapse.". In Wermuth C (ed.). Practice of Medicinal Chemistry (Second ed.). Academic Press. pp. 373–386. doi:10.1016/B978-012744481-9/50027-1. ISBN 978-0-08-049777-8.
  5. ^ Gilmanshin R, Dyer RB, Callender RH (October 1997). "Structural heterogeneity of the various forms of apomyoglobin: implications for protein folding". Protein Science. 6 (10): 2134–42. doi:10.1002/pro.5560061008. PMC 2143565. PMID 9336836.
  6. ^ Arai M, Kuwajima K (1996). "Rapid formation of a molten globule intermediate in refolding of alpha-lactalbumin". Folding & Design. 1 (4): 275–87. doi:10.1016/S1359-0278(96)00041-7. PMID 9079390.
  7. ^ Agashe VR, Shastry MC, Udgaonkar JB (October 1995). "Initial hydrophobic collapse in the folding of barstar". Nature. 377 (6551): 754–7. Bibcode:1995Natur.377..754A. doi:10.1038/377754a0. PMID 7477269. S2CID 4343528.
  8. ^ Vidugiris GJ, Markley JL, Royer CA (April 1995). "Evidence for a molten globule-like transition state in protein folding from determination of activation volumes". Biochemistry. 34 (15): 4909–12. doi:10.1021/bi00015a001. PMID 7711012.
  9. ^ Marianayagam NJ, Jackson SE (October 2004). "The folding pathway of ubiquitin from all-atom molecular dynamics simulations". Biophysical Chemistry. 111 (2): 159–71. doi:10.1016/j.bpc.2004.05.009. PMID 15381313.
  10. ^ Brylinski M, Konieczny L, Roterman I (August 2006). "Hydrophobic collapse in (in silico) protein folding". Computational Biology and Chemistry. 30 (4): 255–67. doi:10.1016/j.compbiolchem.2006.04.007. PMID 16798094.
  11. ^ Paci E, Friel CT, Lindorff-Larsen K, Radford SE, Karplus M, Vendruscolo M (February 2004). "Comparison of the transition state ensembles for folding of Im7 and Im9 determined using all-atom molecular dynamics simulations with phi value restraints". Proteins. 54 (3): 513–25. doi:10.1002/prot.10595. PMID 14747999. S2CID 490838.