An advance in atomically precise
building-block assembly

by Eric Drexler on 2011/05/27

Protein interface design

A paper in Science reports a design method that substantially advances the macromolecular technology base for building atomically precise nanosystems.

Background: foldamer engineering

As many readers know, biology shows an effective way build large, intricate, atomically precise systems: Use covalent chemistry to build chains of small building blocks, and design these chains to fold into nanoscale building blocks that undergo spontaneous assembly driven by Brownian motion and selective binding. This is a key step in climbing a ladder of fabrication technologies that leads to broader, more powerful capabilities.

The covalent synthesis of suitable chains of building blocks* was mastered decades ago, using programmable nanoscale machines that operate in biological systems. Designing structures that fold into compact nanoscale objects has become increasingly routine. Designing these building blocks to assemble, however, has lagged.

The approach

This highlights the importance of the paper in Science.

The authors (from the Baker lab, and I’m tempted to add “of course”) used RosettaDesign-based protein engineering tools to design proteins with surface structures that bind to a natural protein at a particular location, and with a particular orientation. Finding a protein that binds isn’t too hard — screening and evolutionary methods applied to antibodies (among other proteins) can do this — but achieving high affinity (tight binding) in a specific geometry is new.

They achieved this by designing binders with the correct geometry but mediocre binding, and then using selection (the equivalent of antibody affinity maturation) to refine the interfaces to achieve high affinity. The refinement process retains the initial alignment with good fidelity.

The binding target was a conserved region of the influenza hemagglutinin molecule, hinting at an approach to developing a subtype-independent anti-influenza therapy.

Solving a harder problem than necessary

Note, however, that authors didn’t address the problem of designing building-block interfaces, as an engineer would understand the task: They did something harder. Only side of the interface was designed to bind, while the other was a naturally occurring structure that normally binds nothing.
An engineer designing building-block assemblies, by contrast, would design the interface as a unit, not just one side of it.

It’s easy to see the advantages of being free to tweak both sides to achieve a good fit, to balance solubility and costs of desolvation, and to introduce specific binding interactions (hydrogen bonds, salt bridges, hydrophobic pockets on one side that match hydrophobic side chains on the other, etc.). Freedom to design both sides together also means that protein engineers — when pursuing engineering objectives — can exploit the best-understood motifs, rather than deliberately plunging into the unknown.

In conventional engineering, no one designing a system would freeze the design of one component, and then attempt to mate another to it at a location not designed for the purpose. Interfaces aren’t afterthoughts.

A companion perspective piece for the paper observes that

Although Fleishman et al. have produced a landmark result, it is evident that computational protein interface design is not a solved problem.

For the more symmetric engineering design problem, however, the methods described in the paper can be expected to provide a basis for reliable design tools.

I look forward to seeing the methods and the lab results. This should be low-hanging fruit.


* In other words, peptide foldamers (commonly called “proteins”) which include a range of high-performance engineering polymers.


See also:

{ 10 comments… read them below or add one }

Thomas May 30, 2011 at 3:15 pm UTC

Hi,

This is certainly an interesting discovery. However, it is really that simple to practice the methods derived from computer design tools in a real lab experiment? Would one not suspect there might be unforeseen problems in the practical world? Or is it a case of simply ‘follow the recipe’?

Thanks,

Thomas

Gus June 3, 2011 at 3:15 am UTC

Very impressive.

Eric: you called it right in your 1981 PNAS paper that solving the protein folding problem and designing (or evolving) proteins that are easily designed to fold (without first discovering a deep theory of folding), are separate and distinct problems.

The same is true with designing proteins to tightly bind together; and creating a library of such structures.

At the highest level of funding and research organization, the antiparallel structure of science and engineering should be appreciated. Of course, you can’t have engineering unless you have a goal that you are engineering towards. You can’t have a goal of molecular manufacturing unless you take the position that molecular manufacturing is feasible; something that a number of prominent researchers who are identified as “nanotechnologists” have been reluctant to take a position on.

But the science moves forward….

Eniac July 2, 2011 at 3:43 am UTC

Despite the higher difficulty of designing to an existing interface, as validly pointed out by Eric, it appears to me that the work of the cited paper is an enormous success. “Natural” antibodies generally bind with micromolar affinity, whereas here we are reaching into the nanomolar range, up there with most therapeutic drugs. Antibodies are nature’s best attempt at this task, and besting her several orders of magnitude could rightly be seen as a triumph, with important applications in molecular biology and medicine. Injecting goats and rabbits for antibodies may soon become antiquated.

As to Thomas’ concerns, it appears the authors have done a thorough job at carrying the work to conclusion in the real world, with the affinity data showing clearly and beyond doubt that the method works, and structural data showing it works the way it was intended.

Now if we can similarly design the other end of the protein to, for example, bind to and activate a killer T-cell receptor, we may have a powerful and versatile new therapeutic tool in hand, improving on the immune system and exploiting it at the same time.

Eniac July 2, 2011 at 3:55 am UTC

I see that Corn and Baker have a current address at Genentech. Must be a very new development, as this affiliation does not appear to be apparent from the Genentech web-site. Perhaps the practical implications have already found a conduit towards realization, here…

Eniac July 2, 2011 at 4:02 am UTC

Never, mind, I misread the symbols. It is only Corn who is at Genentech.

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