Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
3.5.8 Ligand-Receptor Mapping
To achieve a fully general-purpose receptor capability in nanomedical systems, two classes of analytic function are essential.
First, presented with an arbitrary molecule, the system or user must be able to infer from the molecule's structure the shape and electronic configuration of an optimal receptor geometry that will efficiently bind it, with a particular affinity and specificity (as a design specification). This discovery procedure may involve a process akin to molecular imprinting (Section 126.96.36.199), fluorescent dye affinity matching on testing chips (Chapter 20), Structure Activity Relationships (SAR) by NMR techniques,424 or pin cushion receptor mapping (Section 188.8.131.52).
Second, presented with an arbitrary protein-built binding site embedded in living tissue, the system or user must be able to infer the molecule(s) which the given receptor could bind, and to compute the affinity and specificity of that activity. This capability may require a rather diverse steric toolkit. Biological receptors are constructed in one of ~500-1000 distinct shapes or "domains," such as the well-known Y-shaped antibody immunoglobulin domain (~100 residues) and other assorted clefts, folds, kringles and coils. Several hundred distinct fold families are known, though it is believed there are only ~20 major domain types,414 and Chothia2604 believes that "the large majority of proteins come from no more than one thousand families."
One mapping technique would employ a series of rodlike probes inserted into the receptor cavity like a pick gun or other lockpicking tool. After physically securing the receptor, the first crude probes quickly map the cavity to nanometer scale. Based on this preliminary information, subsequent probes having ever-finer discrimination chart smaller features as well as charge distributions by inserting a predetermined set of test rods with functionalized tips in a standard sequence, to rapidly prune the huge configurational space down to a single unique electrophysical shape using the minimum possible number of tests. (A 1 nm3 volume of multi-element diamondoid receptor structure has ~10148 possible distinct configurations, by one conservative estimate,10 requiring at least 492 binary tests to eliminate all but one configuration. Antibody domains contain ~1050 possible configurations, requiring 166 binary tests.) Cavity Stuffer, a software package comprising an experimental design tool to investigate automated cram-packing of predefined cavities using randomly branched polymers, is a preliminary effort in this general direction,425 although the algorithmic task of discovering an unknown receptor contour may be considerably more challenging.
Another approach to receptor mapping would be the reversible chemical or mechanical denaturation of the receptor protein followed by precise nondestructive amino acid sequencing (Chapter 20), from which tertiary structure and activity could then be computationally inferred. Algorithms to perform such computations are the subject of intense current research interest.952 Even imperfect tertiary structure predictions should greatly reduce the search space, so that only a partial residue sequencing may be necessary for unambiguous identification from a library of possible proteins. Once the target ligand structure has been inferred, the subsequent design and manufacture of receptor-specific agonists and antagonists, including catalysts and cofactors, activators and inhibitors, promoters and repressors, should be comparatively easy.
Last updated on 7 February 2003