Ion Selectivity and Molecular Structure of Binding Sites and Channels in Icosahedral Viruses

This paper begins an attempt to calculate selectivity for those ion binding sites in proteins whose structure is known at atomic resolution. As prototypes for the permeation through pentameric and tetrameric membrane channels, it explores the channel-like structures existing between the pentamers in the protein capsid of four icosahedral viruses of known crystallographic coordinates. These putative channels show two kinds of selectivity filters at their narrowest point: one made up of 5 backbone carbonyl -O’s, the other made up of 5 side chain -OH’s. In view of the generally assumed importance of carboxylate groups in present modelling of binding sites and channels, it is surprising, if these pentameric structures are appropriate models for membrane channels, that not one of them uses side chain carboxylate (or amide) oxygens as ligands for the selectivity filter. Energies underlying binding and permeation are calculated for these putative channels for cations and anions of various charge. Water molecules are included explicitly in the modelling, using microscopic methods developed by Warshel. The present studies go some distance toward providing a quantitative prediction of selectivity and permeation from structural information. They also identify areas of theory and experiment that need extension. Comparisons of the structures and computed energy profiles for the 4 differing viral channels are presented for their intrinsic interest and because the differences from virus to virus should be relatively insensitive to the detailed assumptions of the present modelling. Despite the restriction of the present analysis to “frozen” crystallographic coordinates, intuitively satisfying energy profiles are computed. These profiles reflect a balance between the energy of interaction with the protein and with water molecules in the channel. The factors are examined which contribute to the selectivity between cations and anions and between monovalent and multivalent cations. Channels whose selectivity filters are formed by C=O ligands are emphasized because there is no need to locate ambiguous H atoms; but one example of a selectivity filter composed of a ring of -OH’s is also shown. C=O filters are predicted to be cation selective; but preliminary computations suggest that C-OH filters may prefer anions. Two cases of C=O filters are distinguished: narrow and wide. All cations are more strongly bound by narrow than by wide filters; and a wide filter is predicted to bind cations in inverse relation to their crystallographic radii. In contrast, a narrow filter exhibits sieving according to ion size and is predicted to bind monovalent cations in the K+ selective Eisenman sequence V, K>Rb>Na>Li>Cs, and divalents in the lyotropiC Eisenman sequence I, Ba>Sr>Ca>Mg, independent of the value of partial charge (field strength) of the carbonyl oxygen. In both wide and narrow filters, the selectivity of monovalents vs. divalents depends on field strength: the more negative the partial charge on the oxygen, the more the divalents are preferred. It is also deduced that, though divalent cations bind more strongly than monovalents, they permeate more poorly, which is in agreement with what is observed for the acetyl choline receptor (AChR) channel. The relationship between the equilibrium binding selectivity behavior expected for “frozen” filters and that predicted in previous treatments (10, 13), where ligands are allowed to move and optimize the binding energy, is discussed; as are the implications for kinetic permeation selectivity.