Molecular simulations of ion channels: a quantum chemist’s perspective

Abstract

Molecular dynamics (MD) has become a popular method to study ion channels by theoretical means and to pro- vide new insights into their fundamental properties, such as fast conduction and ion specificity. This Per- spective deals with one of the current challenges of biomolecular MD studies: the accurate description of polarization. Polarization can be defined as the spatial changes in charge distribution due to the presence of an electric field. In the case of ion channels, theoretical studies ought to be able to describe the response of electronic clouds to the moving ions (i.e., ion-induced polarization). However, the most widely used empiri- cal potential energy functions (force fields) such as AMBER, CHARMM, and GROMOS, are not explicitly polarizable, but rather include polarizability implicitly in an average way in their parameterization. Polarizable extensions of these force fields are under active devel- opment, but the lack of in situ reference data that can be used to assess the performance of these force fields renders their development more difficult. Here, we discuss the possible use of quantum mechanics (QM)/ molecular mechanics (MM) simulations to assist the de- velopment of improved force fields for ion channel studies. These QM/MM simulations highlight some of the possible deficiencies of current force fields and pro- vide examples of the importance of polarization for the accurate description of ion conduction and selectivity.