# Ed's Big Plans

## Knots were the wrong math

The Knot Math was eventually understood to be the wrong kind of math to model our problem on.

Knots take the form of a circle that has been broken and rejoined at a point on its circumference after being wrapped about itself an arbitrary number of times. What we’re working on doesn’t utilize any function that twists loops of DNA the same way. The knot maths provide a way to real-value-vectorize these shapes, but do not provide an easy way to insert our own data. There are two properties that relate to the incompatibility. The first is that knot maths consider two knots equal if their topology with respect to the number of twists they have are identical. Our problem does not consider these two knots equal, as distance and sequence specificity (imagine each particle on the rope circle was labeled) are required. Second, what we produce overlaps arbitrarily by lying a circle segment on top of another circle segment whereas the knot maths produce overlaps with twists. While I think there could be a clever way to identify our problem with the knot math, I don’t think there is a feasible or cost (time) effective way to do this.

Brain continues to storm.

I did managed to uncover some very exciting papers however. One of them was on a piece of software called TangleSolve— which does do site specific recombination and visualization of DNA knots– reading on this software was actually instrumental in understanding why our problem was not identifiable here. Side note– topoisomerase — is an enzyme involved with DNA knot formation and super coiling relaxation.

Eddie Ma

September 15th, 2009 at 1:29 pm

## DNA … Knots and Lambdas

A long time ago, one Andre lead a team of students in a journey of mathematical and computational modeling; at the very least, we have reached some useful insights from our tidy trip albeit at a distance from the solution.

Presented here is a very jumbled, very abridged account of the activities of the modeling team this summer and the eventual realization that brings us to now.

The Problem Revisited

So we have a sequence. Actually, two sequences. Actually, we have two loops. Two loops of DNA that will contain a specific sequence used for cassette exchange. The problem is the design of these two loops. We want to design them so that we can predictably exchange specific objects between them. We used an enzyme for recombination that is sensitive to specific sites to perform the exchanges.

The above paragraph is an abstract-abstract of the UW iGem Project.

The Top Down Approach

What I eventually labeled in my mind as the top-down approach is called that in analogy to parsing. In parsing, we build a tree. We can do this conceptually from the bottom-up, or from the top-down. From the bottom-up, we know everything we need to know to build the tree… we know as much as we want to know, we even know if there exists not a tree for this particular string of tokens. From the top-down, we’d have to use some magical induction to chain tokens together by determining a structure that the tokens will find pleasing.

The magical induction of the top-down approach is none other than brute force. There is no magic, just an exponential explosion. The base of this power is the length of the string and the exponent of the power alludes to the complexity and depth of the grammar.

We don’t parse for the sequence problem– that is, we assume the grammar to be irrelevant, that a flat degenerate chain is a sufficient enough tree; we operate on sequences with our enzyme instead.

For our sequence problem, we pick three loops. We see if the first two loops add together with respect to the enzyme to make the third loop. By hand, one is tempted to use various heuristics of deductive logic but it became complicated and soon overflowed the allowed dozen or so objects a human brain may accommodate per instant. The machine was dragged in, and the three loops were shown to it using Python.

We presented three loops of one logical suite of tokens. It ran to completion and to no surprise, this was not our solution. We did this again for all three-loops where each loop is one logical suite. That ran to completion and again, no solution– again to be expected; not yet long enough to accommodate the anticipated length of the solution.

One logical block became two, became three… and at each step, the base of the exponent to our magical induction grew.

Four logical blocks… we halted the experiment; the machine would’ve taken a month to finish that block.

The exponential explosion was real, and our bid that the solution may be just short enough to fit therein was proven false.

The Bottom Up Approach

Months passed, various members went on various summer excursions… and many have returned now. We discuss many theoretical approaches. We resample the problem, sniffing for hints. Actually, it’s been Andre, Jordan and me … we haven’t discussed this with the remaining modeling team yet because of just how vague our new lines of intrigue are. I will revise my opinion if the thought that more individuals means faster solution finding crosses my mind again.

I’ve had a few conversations, one with my MSc advisor, Stefan; one with a friend Andrew Baker; and another with my undergraduate project advisor, Bettina. So far, no one’s seen this specific problem before or can allude to either an approach, technology or research that they’ve seen…

We reformalize the problem with the following constraints as follows.

• Must deal with circularity of DNA, hence by circularly shift invariant
• Must accommodate or encapsulate reverse complementation

Intrigue

Several lines of intrigue we visit now.

First, Knot Theory– provides a representation for knots as real-valued vectors; unique shapes however may produce degenerate vectors. Knots allow us to take our loop of DNA and place the putative recombinatory hotspots one on top of another. Missing from this item is precisely how to dope the vectors with our own sequence data.

Second, Lambda Math and Logical Programming provide a language and a method respectively to map vectors from left to right. The form of the abductive equations for this problem are yet to be discovered however. We’re thinking about this method because we suspect that the recombinase enzyme activity can be completely expressed as a mathematical construct on our doped knot vectors. We hope that this construct can be expressed with abductive statements.

Third, Recombinatory Calculus– actually, this item is in stark competition with Logical Programming as the functional crux of the model. Recombinatory Calculus which is fairly distant from Recombinatorics, mind– is a math that has shown all other math functions can be constructed by just two atoms. If it turns out that the final representation of a DNA loop looks more like arguments for these two atoms, then we may pursue this– but at present, it seems to be losing against Logical Programming– the allure of the two atoms subsides as we realized the complexity for even the addition function for integers.

Direction

Luckily… roughly a dozen papers have been recovered from various repositories that discuss knot math and how to hack it sufficiently to kindly represent DNA loops. We continue to read and discuss these papers until we feel it reasonable to raise it with the entire modeling group… that is, when the science is done and the engineering begins anew.

Eddie Ma

September 4th, 2009 at 9:52 am