Elastic-contractile model proteins: Physical chemistry, protein function and drug design and delivery.

This review presents the structure and physico-chemical properties of ECMPs, elastic-contractile model proteins using sparse design modifications of elastic (GVGVP)(n); it describes the capacity of ECMP to perform the energy conversions that sustain living organisms; it arrives at the hydration thermodynamics of ECMP in terms of the change in Gibbs free energy of hydrophobic association, ΔG(HA), and the apolar-polar repulsive free energy of hydration, ΔG(ap); it applies ΔG(HA), ΔG(ap), and the nature of elasticity to describe the function of basic diverse proteins, namely - the F1-motor of ATP synthase, Complex III of mitochondria, the KscA potassium-channel, and the molecular chaperonin, GroEL/ES; it applies ΔG(HA) and ΔG(ap) to describe the function of ABC exporter proteins that confer multi-drug resistance (MDR) on micro-organisms and human carcinomas and suggests drug modifications with which to overcome MDR. Using ECMP, means are demonstrated, for quantifying drug hydrophobicity with which to combat MDR and for preparing ECMP drug delivery nanoparticles, ECMPddnp, decorated with synthetic antigen-binding fragments, Fab1 and Fab2, with which to target specific up-regulated receptors, characteristic of human carcinoma cells, for binding and localized drug release.

Function and frustration of multi-drug ABC exporter protein and design of model proteins for drug delivery using protein hydration thermodynamics.

The mechanism is presented whereby simultaneous hydrolysis of two molecules of ATP in the ATP-binding cassette (ABC) exporter protein, Sav 1866, opens a transmembrane channel to pump drug out of the cell and confers drug resistance, e.g., gives rise to methicillin resistant Staphylococcus aureus, MRSA. The proposed mechanism suggests pharmaceutical design strategies for overloading the capacity of two molecules of ATP to open access to the channel for export. Structural homology of Staphylococcus aureus, Sav 1866, to human P-glyco-protein and MRP2, suggests a similar mechanism could be relevant to human carcinoma cells. The transport mechanism utilizes two thermodynamic quantities -DeltaG(HA), the change in Gibbs free energy for hydrophobic association, and DeltaG(ap), an apolar-polar repulsive free energy for hydration, derived from studies on designed elastic-contractile model proteins (ECMPs). These quantities also allow design of remarkably biocompatible ECMPs as drug delivery vehicles with remarkable control of release profiles and of ECMPs that provide the means of developing pharmaceuticals for blocking multi-drug resistance.