This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Integral membrane proteins are a ubiquitous presence in the mammalian genome, implicated in a diverse array of physiological functions as well as in common disease as a result of their dysfunction. Thus, an exquisitely detailed knowledge of the structure and function of such systems is vital to the development of effective therapies treating such dysfunction. Complementing experimental efforts, molecular modeling approaches have allowed a superbly detailed picture of membrane protein structure and function to emerge. Despite the successes to date, there are still outstanding issues in the application of modeling approaches to investigating membrane and membrane protein systems. Modeling approaches require underlying potential models, or force fields, to describe the necessary physics of interactions between individual particles within the many-body systems. Of particular note are electrostatic interactions which are treated in a pair-wise Coulomb fashion with interacting sites assigned a fixed charge derived via quantum mechanics. The validity of this approach breaks down, however, for processes where polarization allows for response of the molecular charge distribution to changes in local environment (electric fields). From a physiological view, an accurate theoretical description of molecular recognition processes such as those involved with ion permeation energetics and selectivity in biological ion channels, implicated in myriad physiological functions and disease, require an accounting of such effects. The current proposal discusses research aiming to study ion permeation energetics in ion channels, with particular focus on the effects of non-additive contributions. To address project aims, the Principal Investigator will develop novel polarizable force fields for proteins, lipids, and membrane bilayer components and a series of monovalent ions. This will involve application of a combination of quantum mechanical and classical simulations. These models will then be applied to calculations of the free energy surfaces underlying ion permeation in order to assess the influence of polarization in describing this class of recognition processes. The goal will be to predict the underlying free energy surface to sufficient accuracy to allow quantitative estimation of experimental ion currents through simple channels. The work will then be extended to study polarization and charge transfer effects in the KcsA potassium channel.
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