Hydrophobic collapse

Hydrophobic collapse is a hypothesized event that occurs during the folding process of globular proteins, suggested on the basis of the observation that proteins' native states often contain a hydrophobic core of nonpolar amino acid side chains (interspersed with charged side chains that are neutralized by salt bridges) in the protein's interior, leaving most of the polar or charged residues on the solvent-exposed protein surface. The energetic stabilization conferred on the protein by the sequestration of the hydrophobic side chains from the surrounding water is thought to stabilize folding intermediates. The hypothesis generally posits that hydrophobic collapse is relatively early event in the folding pathway, occurring before the formation of many secondary structures and native contacts present in the fully folded tertiary structure. The collapsed intermediate is also referred to as a molten globule and corresponds to a partially folded state whose energy is lower than that of the denatured state but higher than that of the native state - that is, within the energy well of the folding funnel but not yet close to the energy minimum.

Partial hydrophobic collapse is an experimentally accepted model for the folding kinetics of many globular proteins, such as myoglobin, [Gilmanshin R, Dyer RB, Callender RH. (1997). Structural heterogeneity of the various forms of apomyoglobin: implications for protein folding. "Science" 6(10):2134-42. ] alpha-lactalbumin, [Arai M, Kuwajima K. (1996). Rapid formation of a molten globule intermediate in refolding of alpha-lactalbumin. "Fold Des" 1(4):275-87.] barstar, [Agashe VR, Shastry MC, Udgaonkar JB. (1995). Initial hydrophobic collapse in the folding of barstar. "Nature" 377(6551):754-7.] and staphylococcal nuclease. [Vidugiris GJ, Markley JL, Royer CA. (1995). Evidence for a molten globule-like transition state in protein folding from determination of activation volumes. "Biochemistry" 34(15):4909-12. ] 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. [Marianayagam NJ, Jackson SE. (2004). The folding pathway of ubiquitin from all-atom molecular dynamics simulations. "Biophys Chem" 111(2):159-71.] [Brylinski M, Konieczny L, Roterman I. (2006). Hydrophobic collapse in (in silico) protein folding. "Comput Biol Chem" 30(4):255-67.] Globular proteins that are thought to fold by hydrophobic collapse are particularly amenable to complementary computational and experimental study using phi value analysis. [Paci E, Friel CT, Lindorff-Larsen K, Radford SE, Karplus M, Vendruscolo M. (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. ]

References