MOLECULAR CARTOGRAPHY OF GLOBULAR PROTEINS (ANTIGENIC SITES).

摘要

Great interest is focused on the surface of globular proteins. Important chemical phenomena such as ligand binding, denaturation and hydration depend on stereochemical interactions that take place there. A number of investigators have devised quantitative representations of the surface of proteins of known structure. In these representations the surface is mapped by systematically tracing the van der Waals envelope of the protein with a water-sized spherical probe. These methods demonstrate that the surface of proteins is pitty, with surface topographic features of molecular dimension. However, existing methods do not treat this variegated surface topography in quantitative detail nor do they distinguish between local and global features.;The molecular surface and antigenic properties of two proteins of known three-dimensional structure, sperm whale myoglobin and hen egg-white lysozyme, are studied in detail. No structural criteria can be found to distinguish antigenic from nonantigenic regions of the surface. Indeed, the results suggest the entire surface of a protein is potentially antigenic. A strong correlation is found between reported antigenic regions and the globally most exposed portions of the protein surface. An antigenic matrix composed largely of the most exposed residues in the protein is proposed to explain the correlation.;Finally, molecular cartography is used to examine whether antibodies selectively bind the most mobile regions of the protein. A stronger correlation is found between antigenicity and global exposure than is found between antigenicity and mobility, suggesting that global accessibility may be a major factor in antibody binding. The perceived correlation between mobility and antigenicity is likely a consequence of globally exposed regions having higher than average mobilities because they are less constrained by surrounding atoms.;Molecular cartography is introduced as a method of quantitating the three-dimensional topography of the protein surface by contour mapping. A contour map preserves local topographic features of an irregular object while simultaneously presenting a global view of its surface. The method is applied to the problem of describing antigenic determinants on the surface of proteins.