| Sumario: | Interactions between metal ions and π systems (metal-π interactions) are known to confer significant stabilization energy. However, in biological systems, few structures with metal-π coordination have been determined; thus, its roles must still be elucidated. The cation-π interactions are not correctly described by current molecular mechanics even when using a polarizable force field, and thus they require quantum mechanical calculations for accurate estimation. However, the huge computational costs of the latter methodologies prohibit long-time molecular dynamics (MD) simulations. Accordingly, we developed a novel scheme to obtain an effective potential for calculating the interaction energy with an accuracy comparable to that of advanced ab initio calculations at the CCSD(T) levels, and with computational costs comparable to those of conventional MM calculations. Then, to elucidate the functional roles of the Natphenylalanine (Phe) complex in the catalytic site of Ti lipase, we performed MD simulations in the presence! absence of the accurate Nat-π interaction energy. A comparison of these MD simulations revealed that a significantly large enthalpy gain in Na-Phe16 substantially stabilizes the catalytic site, whereas a water molecule could not be substituted for Na for sufficient stabilization energy. Thus, the cation-π interaction in the lipase establishes a remarkably stable core structure by combining a hydrophobic aromatic ring and hydrophilic residues, of which the latter form the catalytic triad, thereby contributing to large structural changes from the complex with ligands to the free form of the lipase. This is the first report to elucidate the detailed functional mechanisms of Nat-π interactions.
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