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
3.5.9 Large Molecule Binding, Sorting, and Transport
Is there any size limit for target molecules to be transported? Natural receptors have already been found for large molecules including low-density lipoproteins (LDLs) > 1,000,000 daltons426 and high-density lipoproteins (HDLs).1038
The methods described in earlier Sections can be adapted for binding large molecules (>1000 atoms; Fig. 3.15), including molecules far wider than the binding device itself (e.g., ~200-nm diameter virus particles and larger). Making a binding site for a large molecule should be physically easier (albeit computationally more challenging) than making a binding site for a small molecule because of the greatly increased area of interaction. For example, a binding energy of 400 zJ may be realized by creating a dispersionforce binding area covering only ~25% of the surface of a 10,000-atom target molecule (Table 3.6) or a mere ~0.02% of a 200-nm virus particle.
This makes possible the concept of binding pads -- small surfaces with dimples (concave or convex), each dimple consisting of precisely-placed nanometer-scale features that are complementary to specific patches (e.g., epitopes) on the surface of the large target molecule. (Specificity is lost for portions of the molecule outside the particular patches.) Each dimple could effectively grasp the side of the large molecule without having to fully enclose it -- a capability useful in nanorobot foot pads during cell walking and anchoring (Section 9.4.3), in handles for nanociliary or nanomanipulator transport functions (Section 9.3.2), and for chemotactic sensing (Section 4.2.6). (For example, macrophage receptors for LDLs employ a "pad" consisting of three globular cysteine-rich domains.426) The large compliance of target protein molecule subunits should prove curative for any misalignment problems caused by cumulative small errors in bond lengths across large diamondoid receptor structures.
Rather than using sorting rotors, which become unwieldy when large molecule binding pockets must be used, the shuttle pump illustrated schematically in Figure 3.16 may provide reasonably efficient large molecule sortation and transport. The shuttle pump consists of a diamondoid tube within which a receptor ring moves between iris diaphragms at either end (shuttling mechanism not shown). The receptor ring is constructed as two or more binding pad segments. For molecule pickup, the ring is pressed together, forming an annular binding region for the target large molecule, which binds and is shuttled to the other side. The receptor ring is then fragmented, destroying binding affinity and unlocking the target molecule, which escapes via diffusion. The shuttle returns to the pickup side, the receptor is pressed together again, and the cycle repeats. A biocompatible solvent environment is maintained during large-protein manipulation tasks.
Assuming a roughly spherical large molecule and laminar fluid flow at 1 atm forcing pressure (Section 9.2.7), a 10-nm diameter molecule moves through a 20-nm long pump (~10-20 kg, ~106 atoms) in ~10-6 sec at ~0.02 m/sec, consuming ~0.02 pW during transfer. A 200-nm virus-size target molecule moves through a 400-nm long pump (~10-17 kg, ~109 atoms) in ~10-2 sec at ~60 microns/sec, consuming ~10-16 watts during transfer; at ~0.0002 atm, release time is diffusion limited. The transfer force exerted on a 10-nm molecule is ~1 pN, ~600 pN on a 200-nm virion; a binding energy of 400 zJ at a 0.2-nm contact distance gives a binding force of ~2300 pN, sufficient to hold a particle of either size firmly during transport and release.
J. Soreff points out that as protein size increases, so does the energy available for local minima in the binding. Desired proteins may become stuck in incorrect positions, or undesired proteins may become partially adhered to a receptor. Besides designing to minimize these possibilities, using a multireceptor cascade with different combinations of binding patches at each stage should allow complete exclusion of undesired large-molecule species.
Last updated on 7 February 2003