A Revolution
in de novo Protein Engineering Methodology

by Eric Drexler on 2009/03/30

An engineered protein
The product of
a new design methodology

“Design and engineering
of an O2 transport protein”
R L Koder, et al.
Nature, 458: 305–309 (2009).

In a recent Nature article, researchers describe the design of a peptide foldamer device (a.k.a. “protein”) that binds and releases oxygen in a way that resembles the heme protein, neuroglobin — and they focus more on the design process than on the design product. They advocate an engineering approach that explicitly rejects aspects of the biological model.

I have long argued that, while nature offers inspirations for molecular engineering, close adherence to natural models is often intellectually and technologically crippling.

Protein engineering is often approached as if it were part of biology. Imagine approaching aerospace engineering as if it were part of ornithology: Although the pioneers of human flight learned a lot about wings from birds, if they had waited for success in making artificial feathers and artificial muscle, we’d still be on the ground.

As the researchers say about the case at hand:

The principles of natural protein engineering are obscured by overlapping functions and complexity accumulated through natural selection and evolution. Completely artificial proteins offer a clean slate on which to define and test these protein engineering principles, while recreating and extending natural functions.

They note that evolutionary processes don’t necessarily produce results that are clean, modular, and practical as a starting point for engineering:

It has long been recognized that natural selection and evolution build complexity into natural proteins and biological systems….So far, this complexity has severely constrained the ability of protein engineers to approach the efficiency of natural protein catalysts. However common it may be in nature, we maintain that complexity is not an essential feature of protein as a material, nor is it an essential feature of catalysis….Our approach follows that long used by artists and architects who develop maquettes–simple models that are progressively altered to test and determine the ultimate characteristics of their constructions.

Their paper, “Design and engineering of an O2 transport protein”, describes the design process step by step, from simple framework to finished product. Along the way, they introduce components that bind the central functional device, heme; components that facilitate NMR characterization of structures (this is called “design for test”); structural features enabling motions that result in cooperative binding of multiple O2 molecules; and structural features that protect the active center from harmful interactions with water.

In the end, they point out that this work refutes the widespread perception that delicate and complex natural structures — merely because they exist — are necessary:

The ease with which globin-like properties can be reproduced in a completely unrelated and simply engineered maquette indicates that the relatively complex globin fold is for the most part unremarkable, and may be common in nature not because of a uniquely capable design for oxygen binding, but simply because it is good enough.

Scientists have repeatedly expressed doubt about the feasibility of designing molecular machine systems, simply because we don’t yet understand how to replicate natural ones. Again and again, experts have committed the elementary fallacy of equating what is sufficient with what is necessary.

The list of similar fallacies and misjudgments about the basic nature of molecular engineering is both long and (quite literally) oppressive. Perhaps contemplation of results like these will be liberating.

See also:

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