Present-forward development

Up: Bridging the gaps
Complementary: Future-backward development

Here counting to "future-forward development" will be everything that is already investigatable by experimental means that are accessible today (more or less widely/costly).

There are basically two fields that need pushing:

• Improving on various foldamer technologies (self-assembling and self-folding)
• Prototyping of very early forms of force applying mechanosynthesis

And looking maybe a bit into the future:

• Manipulating (and assembling!) self-assembled foldamers bricks with scanning probe tips
• Integrating the learned mechanosynthetic capabilities into the learned foldamer capabilities (likely in solvent first)

Areas

Foldamer Technology

Needed is:

• Development of new and
• improvement on existing foldamers technologies

With a particular focus on:

• stiffness
• modular reusability
• separation of concerns
• eventual integration of mechanosynthetic aspects (more or less direct)

To give concrete targets:

(1) Getting to prismatic or otherwise larger scale highly geometric construction bricks that can be be connected in a programmable fashion by self assembly. Or later eventually by guided self assembly or even .... process.

(2) Eventual integration of mechanosynthetic tips for the other development path.

There are foldamer technologies with different degrees of stiffness.

• Low stiffness (most scaleable it seems)
• mid stiffness
• high stiffness (least scaleable is seems)

It may be possible to combine these (insetting the stiffer in the less stiff ones) and the fastest progress combining the best of all worlds. Or one of the stiffer technologies unexpectedly starts scaling better.

Low stiffness foldamer technologies

Of main interest here may be the Structural DNA nanotechnologies (SDN).
Especially the DNA-brick kind of SDN. That is: Cuboid blocks from many short DNA oligimer staples.
Main page: Structural DNA nanotechnology

Main limitations are:

• not stiff enough for atomically precise placement of anything (with an asterisk).
• programmable attachment points are spaced apart quite far.
• there are pretty big error rates (there is no cell machinery that is helping selfassembly along)
• rapidly dropping yields when going to bigger structure sizes.

Main strengths: It is the foldamer tech …

• … with the largest number of shape-addressable individual sites in an assembly
• … with the most control beyond infinite translatory or rotatory symmetries

The asterisk:

Atomically precise placement via SDN actually has been demonstrated. But only in a time averaged way. Isn't that completely useless? Actually not. As known from statistics one can switch out a temporal average for an spacial average. But how can that be done in an engineering setting?

By integration of a smaller piece of stiffer foldamers (like de-novo proteins) foldamers into a larger piece of the SDN structure (less stiff foldamers) one can average out spacially over all interface attachment points.

That is easier said than done tough. In fact this is probably extremely difficult and necessitates great advances on both involved foldamer technologies. The surrounding and the inserted one. To have sufficient spacial averaging over thermal vibrations the interface surface needs to be large and stiff enough.

Why not just use the stiffer foldamer technology (e.g. de-novo proteins) to begin with? Because it may be (and looks like so) that the stiffer foldamer technologies are more difficult to scale to a necessary size, that it is to couple it so a less stiff but more scalable different foldamer technology.

So in summary:
SDN may be usable as low stiffness very large scale backbone structure for higher stiffness large insets that then do the actual small scale atomically precise holding.

(wiki-TODO: add a sketch of that idea here)

Mid stiffness foldamer technologies

Of main interest here may be de-novo protein engineering.
In particular packed alpha helix bundles and beta sheets are of special interest because of:

• their higher stiffness
• their higher geometry
• their higher folding predictability

High stiffness foldamer technologies

One promising candidate here may be Spiroligomers.

These have their individual monomers (base building blocks) linked together by not just one but by two inter-atomic bonds. This prevents free rotation around single sigma-bonds. Thus:

• the structures are likely notably stiffer than proteins.
• there is no folding foldamer folding involved (actually these are not exactly foldamers anymore)

The shape is pretty much uniquely given by sequence of monomers that where linked together.

Limits to increased stiffness:

• intentional bi-stable snap flips or such may be possible to include on purpose.
• long chains might bend a lot to the point of self-entanglement
• side-stacking issues

Side-stacking: Since there is no folding present to archive volumetric structures it is necessary to stack these spiroligomers sidewards/sideways by some different post processing method. Final structure stiffness may largely depend on how tight one can stack them sideways. The higher stiffness along the chain might even be counterproductive here. That is reduce the sidewards stiffness.

(Note that this is somewhat speculative. The author has never worked with Spiroligomers.)

Fat fingers

Here's a motivational/economic problem:

There are two factors that space out the thermal motion overpowering holding sites stongly:

• separation of concerns by geometric brick modularization
• the afore described approach of stiffer-foldamer in less-stiff foldamer insets

This spacing …

• … is not exactly a problem for far term applications. See fat finger problem.
  
• … is a problem for near term applications - elaboration follows

spacing caused by pushing for modularization

Take a typical proteins(enzymes) active site (the pocket where molecules get bound and manipulated). When one switches out just one single side-chain "finger" with an other one that has a slightly different shape, then everything else may change with it. Change the shape of one finger slightly and this shape-change propagates to many other (more or less adjacent) ones in highly unpredictable ways.

Through tight packing of the side-chains all the (alone floppy) fingers provide all the other ones mutual support against too big thermal vibrations and against fatal displacements through free rotations.

Changing the structure of "fingers" enough
(e.g. by switching them out through stiff artificial interlinked side-chains packs or spiroligomer packs),
such that they can keep their position sufficiently precisely without the need for "mutual support sideward packing" makes them so big/fat that only very few fingers can reach in on specific point on a target molecule. Certainly not enough to pick out a molecule based on shape.

This is a problem for near term applications.
This would be a-ok for advanced mechanosynthesis where …

• … molecules to synthesize start out and stay in machine-phase - nothing big and complex needs to be catched from solvent
• … chain polymers can eventually be syntesized by holding them in a "two point stretched out" fashion
• … there is a focus on just a few base simple materials for metamaterials -- and moreover these are crystalline
• …

Effects of very big spacing through foldamer in foldamer insets (pushing for stiffness)

Really far apart spacing like in the case of the proposed foldamer in foldamer insert also comes with another effect. Whatever these stiff-fingers/tips do they do it slower because there are fewer of them around per fixed volume.

This eventually can be compensated through added active motion and applied mechanical forces like:

• higher reaction success rate nearing one -- instead of like e.g. 1 in 1000 reacts on any given attempt
• increased reaction speeds during the reaction -- if this is was a limiting factor
• increased reloading speed -- this may be limited as long as operations are conducted in a solvent rather than a vacuum

See Mechanochemistry

Loss of combinatorial power while gains are not yet harvest-able

The capability of easily trying a huge number of random mutations is a powerful tool for many of today's medical applications. Like e.g. detection of small molecules.

Fighting against conflation of concerns and for modularization for the sake of getting to more advanced forms of APM ASAP requires stiffening the sidechains/fingers/tips. This in turn requires spreading out the fingers. The fingers that are now spaced apart much more become unable to collaborate in huge number on the same local section of a small molecule. So the power for near term application in this regard is lost.

Experimentally accessible very early forms of force applying mechanosynthesis

This has been done on silicon. (wiki-TODO: add details here)

Prototyping of self replicating robotics

This is borderline present forward.
While prototyping of self replicating robotics is indeed already experimentally accessible (has been since ages) it is not possible yet to do such prototyping at the final target scale the nanoscale.

Doing prototyping at a scale different than the target scale needs one to always keep strong eye on the different physics at the nanoscale.
See: Applicability of macro 3D printing for nanomachine prototyping
See: RepRec pick and place robots

This is probably the most accessible area of present forward development for low level funding private independent agent work.

Equipment, accessibility, cost

Here is a hugely incomplete list of some of the most relevant experimental equipment.
Plus notes on its accessibility and cost of usage.
For who can afford what see: Funding contexts and their degree of viability

(wiki-TODO: each of these following technologies deserves its own main article)

Foldamer synthesis

• There are already services that provide basic foldamers.
• There are already services that provide assembly services.
  In the case of DNA e.g. https://www.tilibit.com/

Prices for limited amounts can be surprisingly cheap. But this can quickly rise with when a lot of combinatoric variants are needed.

Also more advanced (stiffer/smaller) foldamer technologies are typically more expensive and less accessible.
Proteins seem somewhat less accessible than structural DNA nanotech.
There are no spiroligomer synthesis services as of today (2021 to check)

Scanning probe microscopes

There are three major price levels:

• Full on DIY scannig probe microscopes (mostly STMs barely AFMs)
• Small relatively cheap commercial scanning probe microscopes
• Big expensive commercial systems

Most well known are electrically operaating STMs and mechanically operating AFMs

• STMs reach atomic resolution most easily (due to the highly nonlinear behaviour of the tunnelling current)
• STMs are limited to electrically conductive surfaces
• AFMs reach atomic resolution harder - especially for cheap DIY approaches this has not be demonstrated
• AFMs made some of the highest resolution images of flat polyaromatic hydrocarbon molecules by 2021 though. (wiki-TODO: investigate there and add insights here)

Generally there are many more types of scanning probe microscop.
Each defined by whnat physical quantity they probe. Magnetic, Optic, ...

There is one particular versatile technology that combines the best of several technologies.

Transmission electron microscopy

Very expensive.

• Especially of interest is Tomographic Cryo-EM.
• One severe limitation is that for really high resolution there is an average over many identical parts involved
• Highly recommendable are the introductory videos by Grant Jensen (Caltech)

Associated technology: Plunge freezing

• hard to miniaturize
• hard to automatize
• limited degree of parallelizability

X-ray structural analysis

Rather expensive to very expensive.

• desktop (cathode ray tube) devices
• accelerator beam lines
• free electron lasers

Magnetic resonance structural analysis

• Access to synthetic equi
• Access to analytic equipment

Related

• Foldamer R&D
• R&D in constructive/additive use of Scanning probe microscopy
• Funding contexts and their degree of viability
• Present-forward Future-backward overlap