A mechanism for rotamase catalysis by the FK506 binding protein (FKBP)

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Abstract
A detailed mechanism for the catalysis of prolyl isomerization by the rotamase enzyme FKBP is proposed on the basis of a model constructed from the known structure of the FK506/FKBP complex. The model substrate is bound as a type VIa proline turn with the ends exposed to permit longer polypeptide chains (e.g., protein loops) to act as substrates. An ab initio potential for the isomerized imide bond is combined with a molecular mechanics representation of the rest of the system to calculate the reaction path. The resulting activation energy for the enzymatic cis-->trans isomerization is equal to about 6 kcal/mol, in good agreement with experiment. The lowering of the barrier relative to the solution value of 19 kcal/mol is found to arise from a combination of desolvation of the imide carbonyl, ground-state destabilization, substrate autocatalysis, and preferential transition-state binding. Minimal rearrangements are required in the enzyme and the substrate along the reaction path. The enzyme residues that participate in catalysis agree with the available mutation data. The type VIa turn model corresponds to a sequence-specific structural motif commonly found on the surface of proteins. It is likely to have a role in the formation of protein complexes with FKBP-like domains that function as foldases or chaperones.

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