A novel computational method incorporates the molecular details of transmembrane proteins into the quantitative evaluation of lipid-protein interactions and their mechanistic role

Physiological function requires modulated communication across the cell membrane, mediated in part by proteins that span the membrane with multiple transmembrane segments (TM), e.g., 7-TM receptors (GPCRs), transporters, and ion channels. While the effects of these proteins propagate across multiple spatial and temporal scales to cause physiological responses, they themselves are activated and modulated at the molecular scale. For example, the activation of the 7-TM receptors has been shown to occur via changes in the conformation of the molecule, predominantly a movement of particular TMs, viz. TM5 and TM6. This dissertation evolves a quantitative understanding of how such molecular mechanisms of multi-TM proteins involve the participation of their membrane environment. The cost of the adaptation of the membrane to the protein is evaluated in terms of the energy cost for membrane remodeling near the protein. In previous studies (Huang, Biophysical J 1986; Nielsen et al., Biophysical J 1999), this energy cost could explain experimental observations of the role of the membrane in the function of model single-TM peptides like gramicidin A ion channels, at a quantitative level. To quantify the energetics for multi-TM proteins taking into account their relevant molecular details, a new hybrid Continuum-Molecular Dynamics (CTMD) method is developed. This novel method uses the experimentally validated continuum approach for quantifying the energetics of membrane remodeling near the protein, but in combination with a molecular description of the lipid-protein interface from cognate Molecular Dynamics simulations. Thus, it takes into account the structural and dynamic conformational properties of multi-TM proteins, making it possible to quantitatively investigate the role of the membrane in their molecular mechanisms. This is illustrated for the activation and oligomerization of 7-TM receptors, and the substrate transport of neurotransmitter transporters. The illustrative applications reveal specific molecular regions involved in energetically significant interactions with the membrane, and demonstrate that local, energetically costly interactions are mechanistically important. The applications show as well how these interactions differ for lipid compositions having different physico-chemical properties, thus placing the mechanistic role of the membrane in the context of the compositional heterogeneity of the cell membrane.