The role of hydrophobic interactions in initiation and propagation of protein folding

Abstract

Globular proteins fold by minimizing the nonpolar surface that is exposed to water, while simultaneously providing hydrogenbonding interactions for buried backbone groups, usually in the form of secondary structures such as ␣-helices, ␤-sheets, and tight turns. A primary thermodynamic driving force for the formation of globular structure is thus the sequestration of nonpolar groups, but the correlation between the parts of proteins that are observed to fold first (termed folding initiation sites) and the ''hydrophobicity'' (as customarily defined) of the amino acids in these regions has been quite weak. It has previously been noted that many amino acid side chains contain considerable nonpolar sections, even if they also contain polar or charged groups. For example, a lysine side chain contains four methylenes, which may undergo hydrophobic interactions if the charged -NH 3 ؉ group is saltbridged or hydrogen-bonded. Folding initiation sites might therefore contain not only accepted ''hydrophobic'' amino acids, but also larger charged side chains. Recent experiments on the folding of mutant apomyoglobins provides corroboration for models based on the hypothesis that folding initiation sites arise from hydrophobic interactions. A near-perfect correlation was observed between the areas of the molecule that are present in the burstphase kinetic intermediate and both the free energy of formation of hydrophobic initiation sites and the parameter ''average area buried upon folding,'' which pinpoints large side chains, even those containing charged or polar portions. These results provide a putative mechanism for the control of protein-folding initiation and growth by polar͞nonpolar sequence propensity alone.folding pathways ͉ myoglobin ͉ ribonuclease F reed of the ribosome, and in the absence of chaperones, a newly synthesized protein exists in an ensemble of states, the so-called statistical coil, the nature of which is a subject of much recent investigation (1). It subsequently folds to the native biologically active structure whose free energy is considered to be a minimum under appropriate solution conditions (2). Since the seminal work of Anfinsen (2), the kinetics of the folding process and the final structure have been considered to be determined by the physical interactions among the amino acid residues to attain the thermodynamically favored state.A major question has involved the exact mechanism by which the interresidue interactions specify the initiation of folding in the unfolded polypeptide chain under folding conditions. Because nonpolar groups are not soluble in water, attention has been focused on the hydrophobic interactions between nonpolar side chains to achieve their sequestration from aqueous solvent. A model has been proposed in which nearby nonpolar groups in the chain participate in hydrophobic interactions with minimal loss of entropy of the chain because of the proximity of the interacting side chains in the amino acid sequence (3).Yet the chemical nature of the polypeptide chain complicates ...

Deep mutational scanning of an RRM domain of the Saccharomyces cerevisiae poly(A)-binding protein

“…These results suggest that both polarity and the nonpolar neck of K156 are required for its function (Dyson et al 2006). In the human PABP-1 RRM2, the residue equivalent to K156 is involved in packing interactions between RRM1 and RRM2, which stabilize the RNAbinding trough (Deo et al 1999).…”

Structural characterization of partially folded intermediates of apomyoglobin H64F

“…The AABUF profile of apomyoglobin provides an explanation for the observed folding pathway and for the structure of the burst phase folding intermediate. It was also shown that the AABUF profile could be changed by mutagenesis to alter the kinetic folding pathway by design (Nishimura et al 2005b;Dyson et al 2006). However, for the H64F mutant, the observed change in the structure of the folding intermediate does not seem to arise from changes in the AABUF as a result of the mutation of His to Phe but rather from stabilizing hydrophobic interactions in the compact molten globule states.…”

Revisiting the Carboxylic Acid Dimers in Aqueous Solution: Interplay of Hydrogen Bonding, Hydrophobic Interactions, and Entropy

“…Considering a dimerization/binding reaction A + B ⇌ AB, the absolute binding constant is defined as 16 (2) where C i is the concentration of species i and C0 is the standard concentration in the same units as C i . The subscript "D" stands for dimerization.…”