Nanomedicine

National Center for Design of Biomimetic Nanoconductors

2006 Progress Report – Executive Summary

The theme of our Nanomedicine Development Center is design of biomimetic nanoconductors and devices utilizing nanoconductors. The model theoretical systems are native and mutant biological channels and other ion transport proteins and synthetic channels, and heterogenous membranes containing channels and transporters. The model experimental systems are engineered protein channels and synthetic channels in isolation, and in self-assembled membranes supported on nanoporous silicon scaffolds. The ultimate goal is to understand how biomimetic nanoscale design can be utilized in devices to achieve the functions that membrane transport accomplished in biological systems: a) Electrical and electrochemical signaling, b) generation of osmotic pressures and flows, c) generation of electrical power, and d) energy transduction.

Our Center's broad goals are:

• To advance theoretical, computational, and experimental methods for understanding and quantitatively characterizing biomembrane and other nanoscale transport processes, through interactive teams doing collaborative macromolecular design and synthesis, computation/theory, and experimental functional characterization.
• To use our knowledge and technical capabilities to design useful biomimetic devices and technologies that utilize membrane and nanopore transport.
• To interact synergistically with other workers in the areas of membrane processes, membrane structure, biomolecular design, biomolecular theory and computation, transport processes, and nanoscale device design.
• To disseminate enhanced methods and tools for: theory and computation related to transport, experimental characterization of membrane function, theoretical and experimental characterization of nanoscale fluid flow, and nanotransport aspects of device design.

Our Center’s initial design target is A biocompatible biomimetic battery (the "biobattery") to power an implantable artificial retina, extendable to other neural prostheses. Broad design principles are suggested by the electrocyte of the electric eel, which generates large voltages and current densities by stacking large areas of electrically excitable membranes in series. The potential advantages of the biomimetic battery are lack of toxic materials, and ability to be regenerated by the body's metabolism.

The development and maintenance of the electrocyte in the eel are guided by elaborate and adaptive pathways under genetic control, which we can not realistically hope to include in a device. Our approach will include replacing the developmental machinery with a nanoporous silicon scaffold, on which membranes will self-assemble. The lack of maintenance machinery will be compensated for by making the functional components of the biobattery from more durable, less degradable molecules.

Our initial planned specific activities were:

1. Making a detailed dynamical model, including electrical and osmotic phenomena and incorporating specific geometry, of the eel electrocyte.
2. Do initial design of biomimetic battery that is potentially capable of fabrication/self assembly.
3. Search for more durable functional analogues of the membranes and transporters of the electrocyte. Approaches being pursued include designing beta-barrel functional analogues for helix-bundle proteins, mining extremophile genomes for appropriate transporters, chemically functionalized silicon pores, and design of durable synthetic polymer membranes that can incorporate transport molecules by self-assembly. These approaches combine information technology, computer modeling, and simulation, with experiment.
4. Fabrication of nanoporous silicon supports for heterogenous membranes in complex geometries.

Below we describe our initial activities from September 30, 2005 through July 17, 2006, in somewhat general terms, in order not to compromise publication by prior release. For more detailed information, refer to our Web sit for new publications as they come out, and feel free to contact Eric Jakobsson, the Director of the Center, or any of the Center investigators whose information is provided at www.nanoconductor.org/people/.

The Aluru lab has done fundamental detailed simulations on the flow of potassium and chloride in narrow silica channels, taking important quantum effects into account. These simulations will help to guide the fabrication of selective silica channels in the laboratory. They have also shown by computational means at the detailed channel nanofluidics level interesting and novel properties that would arise from parallel channels of arbitrarily different selectivity and permeability, including both generation of electrical potentials and also water transport by osmotic effects. This work may provide insights towards an alternative nanoscale battery design.

The Bayley lab has gathered data on numerous mutations in the alpha-hemolysin channel. These results comprise a wealth of data with which to validate our stochastic dynamics simulation methods, developed by Ravaioli, Roux, and Saraniti. We are also working on making the stochastic dynamics methods more computationally efficient.

The Bayley lab has successfully embedded cyclodextrin into the lumen of the alpha-hemolysin pore in such a manner that the cyclodextrin modifies the channel properties. This is an extremely promising advance in channel engineering. In published work, the Bayley lab has reported that the cyclodextrin imbues alpha-hemolysin with an improved ability to distinguish between bases in nucleic acids as they are passed through the channel lumen, suggesting that this technology may be useful in a method to sequence DNA more rapidly and cheaply. A number of ways are being pursued to use nanopores to sequence DNA---the dextrin/alpha-hemolysin combination in the Bayley lab is one that shows some promise. In our Center, this technology is being developed in the hope of creating robust “designer” ion channels.

The Brinker, Parikh, and Bayley labs are testing various combinations of membrane and support chemistry to find the best combination for durability and function. There is hope that much of the technology that we have been demonstrating in phospholipid membranes can also be extended to more durable cross-linked polymer membranes such as has been developed in the Firestone lab. We are also working on nanofabrication of environments for supported membranes that will be in geometry appropriate for cells of the biobattery, and on new techniques for closely controlling the size of pores in silica films.

The Feller lab is now doing molecular dynamics simulations of a membrane supported by a nanoporous silica film.

The Lavan lab has constructed and is testing a first draft dynamical model of the eel electric organ, which will be adapted for use as a design tool for the biobattery.

The Rempe lab has used quasi-chemical statistical theory and quantum calculations to advance basic understanding of the structural and hydration properties of potassium and sodium ions. These methods will be applied to advancing our basic understanding of potassium and sodium selectivity in channels.

The Scott lab is developing a Self-Consistent Mean Field Langevin Dynamics (SCMFLD) simulation strategy, in which the parameters are derived from earlier atomistic molecular dynamics simulations of the components. Their large goal is to extend the multi-scale approach to the point that thermodynamics and large scale organization and dynamics of highly heterogenous membranes can be predicted from Self-Consistent Mean Field Langevin Dynamics parameterized by atomic scale simulations of the interacting membrane components.

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