Energetic approach to the folding of α/β barrels

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Abstract
The folding of a polypeptide into a parallel (α/β)8 barrel (which is also called a circularly permuted β8α8 barrel) has been investigated in terms of energy minimization. According to the arrangement of hydrogen bonds between two neighboring β-strands of the central barrel therein, such an α/β barrel structure can be folded into six different types: (1) left-tilted, left-handed crossover; (2) left-tilted, right-handed crossover; (3) nontilted, left-handed crossover; (4) nontilted, right-handed crossover; (5) right-tilted, left-handed crossover; and (6) right-tilted, right-handed crossover. Here “tilt” refers to the orientational relation of the β-strands to the axis of the central β-barrel, and “crossover” to the βαβ folding connection feature of the parallel β-barrel. It has been found that the right-tilted, right-handed crossover α/β barrel possesses much lower energy than the other five types of α/β barrels, elucidating why the observed α/β barrels in proteins always assume the form of right tilt and right-handed crossover connection. As observed, the β-strands in the energy-minimized right-tilted, right-handed crossover (α/β)8-barrel are of strong right-handed twist. The value of root-mean-square fits also indicates that the central barrel contained in the lowest energy (α/β)8 structure thus found coincides very well with the observed 8-stranded parallel β-barrel in triose phosphate isomerase (TIM). Furthermore, an energetic analysis has been made demonstrating why the right-tilt, right-handed crossover barrel is the most stable structure. Our calculations and analysis support the principle that it is possible to account for the main features of frequently occurring folding patterns in proteins by means of conformational energy calculations even for very complicated structures such as (α/β)8 barrels.

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