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Abstract
The closed-loop (loop-n-lock) hypothesis of protein folding suggests that loops of about 25 residues, closed through interactions between the loop ends (locks), play an important role in protein structure. Coarse-grain elastic network simulations, and examination of loop lengths in a diverse set of proteins, each supports a bias towards loops of close to 25 residues in length between residues of high stability. Previous studies have established a correlation between total contact distance (TCD), a metric of sequence distances between contacting residues (cf. contact order), and the log-folding rate of a protein. In a set of 43 proteins, we identify an improved correlation (r2 = 0.76), when the metric is restricted to residues contacting the locks, compared to the equivalent result when all residues are considered (r2 = 0.65). This provides qualified support for the hypothesis, albeit with an increased emphasis upon the importance of a much larger set of residues surrounding the locks. Evidence of a similar-sized protein core/extended nucleus (with significant overlap) was obtained from TCD calculations in which residues were successively eliminated according to their hydrophobicity and connectivity, and from molecular dynamics simulations. Our results suggest that while folding is determined by a subset of residues that can be predicted by application of the closed-loop hypothesis, the original hypothesis is too simplistic; efficient protein folding is dependent on a considerably larger subset of residues than those involved in lock formation.
Highlights
Among the theories on protein folding, Berezovsky et al.’s controversial hypothesis, that the basic protein-folding unit is a closed loop with a length of about 25–35 amino acid residues, formed by non-local hydrophobic interactions between the loop ends, is of particular interest [1,2]
Evidence was found to support a preference for loop lengths in protein structures of close to 25 amino acids
The loop length data and the data on the spacing of high force constant residues tie the observation of closed loops of around 25 residues more closely with protein folding because it associates the ends of the approximately 25mer loops with regions of high connectivity and/or rigidity, which are themselves linked with protein folding [37,38]
Summary
Among the theories on protein folding, Berezovsky et al.’s controversial hypothesis, that the basic protein-folding unit is a closed loop (loop-n-lock) with a length of about 25–35 amino acid residues, formed by non-local hydrophobic interactions between the loop ends, is of particular interest [1,2]. Current evidence for closed loops (defined in part by a close approach in space of residues some distance apart along the polypeptide chain) comes from several observations, all of which point to a common unit of approximately 25 residues These observations include a peak in the distribution of the length of protein chain-returns [1,2], a peak in the number of amino acid neighbours as a function of sequence distance [2], the autocorrelation function of hydrophobic residues [8], and of specific hydrophobic tripeptides [9,10], and the presence of minimally disruptive protein fragments or ‘schemas’, that can be exchanged without loss of
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