Protein knots

I have stumble upon the protein with a very interesting structural motif (PDB ID: 3UN9). Protein subunits forms functional receptor, subunits fit into each other like a pieces of a jigsaw puzzle.

Actually knots are not very rare  in protein kingdom. Take a look for example into databases like pKNOT or knot server from MIT. There is evidence that the artificial knot proteins can be  even successively designed (PDB ID: 3MLG) [1].

But one question arose looking at those type of structure: how this 3-to-1 or 6-to-1 proteins are folded? As it was found knot proteins do not require chaperons for folding, thus folding happens independently under influence of the internal and external conditions: protein itself and cell solution.  Mutations some of the amino acids directly involved in folding do not have great influence thus no "folding features" were found. Some of the knotted structures can be easily unfolded, but methyltransferase structures are very stable under   denaturing conditions. Also interesting to point out that the knots are forming on the late stages of the folding pathway [2].

Attempts to mimic folding in silico was successful [3]. Coarse-grained representation of the protein and simulation of Langevin dynamics for YibK  protein with trefoil knot have shown the early and late knot formation pathways. And as it was expected the hydrophobic aminoacids play the most important role.

One of the most important interests is design of artificial enzymes stable under very harsh conditions for industry.

1. Structure and folding of a designed knotted protein - DOI: 10.1073/pnas.1007602107.
2. Nice review - DOI:10.1088/0953-8984/23/3/033101
3. Attempt to fold knot protein in silico: arxiv.org/abs/q-bio/0611073 


The structure of human soul

Finely, people of Earth solved the mystery of all the times.
They found the structure of soul, the precious tiny material of every or mostly every human. It's an x-ray one but an important step is done!


Why ChemInformatics and not ChemOinformatics?

So, finishing the old question "ChemInformatics or ChemOinformatics". I decided to find official clause for this name.
Origin of Cheminformatics seems to be originated from Obernai declaration that states use of the word cheminformatics instead of chemoinformatics. But there is no single document that states it! Even more this declaration use chemOinformatics term!

Some funny notes from molinspiration site:
Date: Fri, 17 Oct 1997 
From: Wendy Warr  
Subject: Re: Cheminformatics/Two new refs. 
I wonder if any of the sources define this awful neologism ("chemoinformatics" 
or "cheminformatics"). Does it really differ from "chemical information" or 
"computational chemistry".

More...from Endy Warr
About two years ago, many people (including myself) considered that
"cheminformatics" was a nasty neologism. My survey this summer shows
that it is now an established discipline, although the tasks involved,
and even the name of the discipline, are not clearly defined yet. 
"Cheminformatics" was preferred to "chemoinformatics" by most

More interesting about Google Ngram comment from the Dalke Scientific blog.

More specifically, if you search for "cheminformatics" you'll see "About 6,960,000 results". Try to go to item 900 and you'll get the message:
In order to show you the most relevant results, we have omitted some entries very similar to the 654 already displayed.
"Chemoinformatics" returns "About 96,500 results". Almost an order of magnitude less! But try going to the end of those and you'll see:
In order to show you the most relevant results, we have omitted some entries very similar to the 671 already displayed.
Shaky indeed!

So, my conclusion is the choice was made by some top molecular modeling people, highly connected to Internet community and the final line was made when Journal of Cheminformatics appearred. From my point of view, chemoinformatics is more correct from grammatical point of view, but the world have some rules.


Chemoinformatics versus Cheminformatics: the other point of view

ChemInformatics or ChemOinformatics? This question is rather old, but I do have my specific point of view.

In Russian (yep, I'm originally from Russia) we are using term chemOinformatics, because it is rather sounds more correctly for the Russian-speaking audience. Because we already have chemometrics, chemotherapy that pronounce more like chimeotherapy, chemoreceptors - oldy term from 60, and many-many others where the sound O in chemO is connecting two consonant letters. That is also true for all the Europe and especially German languages as noted by Egon. The other point is - there is a word chemO that gave birth to many terms in English literature that are chemOgenomics, chemotherapy already mentioned, chemogenesis, chemoreceptors.

Despite typing cheminformatics that can save you 6.25% of typing time, I prefere to use chemoinformatics in unoficial communication, but cheminformatics in official.


CADD successful stories: Part 1.

When browsing CADD journals I always like to read about successful storied lead to development of new drug-like compounds. I think everyone in CADD field like it. I decided to make small resume of these successful examples. You welcome to comment it.

1. Dopamine 1 receptor agonists with selectiviy over D2 receptor

Tools: Homology model, Pharmacophore model, Docking, selectivity by pharmacophore model.
DOI: 10.1002/cmdc.201100546

2. mGluR5 receptor negative nanomolar modulator

Tools: Artificial Neural Network (345 active and 155774 inactive compounds).
DOI: 10.1002/cmdc.201100510

3. Otimization of the omeprazole-based inhibitors of CYP2C19

Tools: pharmacophore, homology model

4. Inhibitors of Eg5 mitotic kinesin

Tools: Pharmacophore search following structure-based virtual screening of 700 000 compounds database. 3 found hits.

5. Inhibitors of ATP  binding  cassette  transporter  ABCC5
Tools: Homology model, structure-based virtual screening. 11 found hits.
DOI: 10.1021/jm2014666

6. Myotonic Dystrophy Type 1 RNA inhibitors

Tools: shape chemical similarity (ROCS), substructural search (RNA motif).

7. Adenosine A2A antagonists

Tools: homology model, structure-based virtual screening (Glide),  Biophysical Mapping 

After finishing I stumble upon excelent examples from Blue Dolphin Discovery. Take a look at them also.


AutoDock Tools bug

AutoDock was always famous for strange file formats, here is funny pdbqt bug.