Have you considered the impact of tunneling? Your rope crossings are not perfect barriers.
On Sat, Jan 20, 2024 at 6:09 PM James Holton <jmhol...@lbl.gov> wrote: > Update: > > I've gotten some feedback asking for clarity on what I mean by "tangled". > I paste here a visual aid: > > > The protein chains in an ensemble model are like these ropes. If these > ropes are the same length as the distance from floor to ceiling, then > straight up-and-down is the global minimum in energy (left). The anchor > points are analogous to the rest of the protein structure, which is the > same in both diagrams. Imagine for a moment, however, after anchoring the > dangling rope ends to the floor you look up and see the ropes are actually > crossed (right). You got the end points right, but no amount of pulling on > the ropes (energy minimization) is going to get you from the tangled > structure to the global minimum. The tangled ropes are also strained, > because they are being forced to be a little longer than they want to be. > This strain in protein models manifests as geometry outliers and the > automatic weighting in your refinement program responds to bad geometry by > relaxing the x-ray weight, which alleviates some of the strain, but > increases your Rfree. > > The goal of this challenge is to eliminate these tangles, and do it > efficiently. What we need is a topoisomerase! Something that can find the > source of strain and let the ropes pass through each other at the > appropriate place. I've always wanted one of those for the wires behind my > desk... > > More details on the origins of tangling in ensemble models can be found > here: > https://bl831.als.lbl.gov/~jamesh/challenge/twoconf/#tangle > > -James Holton > MAD Scientist > > On 1/18/2024 4:33 PM, James Holton wrote: > > Greetings Everybody, > > I present to you a Challenge. > > Structural biology would be far more powerful if we can get our models out > of local minima, and together, I believe we can find a way to escape them. > > tldr: I dare any one of you to build a model that scores better than my > "best.pdb" model below. That is probably impossible, so I also dare you to > approach or even match "best.pdb" by doing something more clever than just > copying it. Difficulty levels range from 0 to 11. First one to match the > best.pdb energy score an Rfree wins the challenge, and I'd like you to be > on my paper. You have nine months. > > Details of the challenge, scoring system, test data, and available > starting points can be found here: > https://bl831.als.lbl.gov/~jamesh/challenge/twoconf/ > > Why am I doing this? > We all know that macromolecules adopt multiple conformations. That is how > they function. And yet, ensemble refinement still has a hard time competing > with conventional single-conformer-with-a-few-split-side-chain models when > it comes to revealing correlated motions, or even just simultaneously > satisfying density data and chemical restraints. That is, ensembles still > suffer from the battle between R factors and geometry restraints. This is > because the ensemble member chains cannot pass through each other, and get > tangled. The tangling comes from the density, not the chemistry. Refinement > in refmac, shelxl, phenix, simulated annealing, qFit, and even coot cannot > untangle them. > > The good news is: knowledge of chemistry, combined with R factors, appears > to be a powerful indicator of how near a model is to being untangled. What > is really exciting is that the genuine, underlying ensemble cannot be > tangled. The true ensemble _defines_ the density; it is not being fit to > it. The more untangled a model gets the closer it comes to the true > ensemble, with deviations from reasonable chemistry becoming easier and > easier to detect. In the end, when all alternative hypotheses have been > eliminated, the model must match the truth. > > Why can't we do this with real data? Because all ensemble models are > tangled. Let's get to untangling them, shall we? > > To demonstrate, I have created a series of examples that are progressively > more difficult to solve, but the ground truth model and density is the same > in all cases. Build the right model, and it will not only explain the data > to within experimental error, and have the best possible validation stats, > but it will reveal the true, underlying cooperative motion of the protein > as well. > > Unless, of course, you can prove me wrong? > > -James Holton > MAD Scientist > > > > > ------------------------------ > > To unsubscribe from the CCP4BB list, click the following link: > https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 > ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list hosted by www.jiscmail.ac.uk, terms & conditions are available at https://www.jiscmail.ac.uk/policyandsecurity/
