The amide bond: pitfalls and drawbacks of the link atom scheme

Methodologies that combine quantum and classical mechanics (QM/MM) are now widely used to study chemical problems in proteins. A small part of the protein (e.g. an amino acid, a side-chain, etc.) is treated quantum mechanically while the remaining part is treated using a classical force-field. The widely used 'Link Atom' scheme (LA) allows to saturate the QM part in a straightforward and easy fashion. This article shows some limitations of the LA scheme (at the ab initio level) when this is applied to systems containing an amide bond that is-or that is close-to the QM/MM frontier. As expected, the 'invisibility' of the link atom from the MM side introduces severe over-polarization effects due to non-balanced interactions. Moreover, in some cases, the resulting QM/MM wavefunction seems unstable with respect to a closed shell → open shell relaxation. © 2003 Elsevier B.V. All rights reserved.