Well, I guess you may have noticed that I don't spend a lot of time on the board these days I have been busy working on firming up the final bits of the Marshall Pathogenesis - the bits that the skeptics still point fingers at
Some of you will know that human protein molecules are in constant motion. Indeed, the NMR/MRI scanners rely upon this motion to image inside your body. They scan the resonant frequencies of water, and several other smaller molecules.
There is a branch of molecular biology which focuses on exploring this motion, and simulating the proteins down to the level of the interatomic forces, as they vary femptosecond by femptosecond (a femptosecond is 10 ** -15 of a second). It takes big computers to play this game, the compute times are horrendous. For example, it took me 10 hours on the fastest available desktop CPU to simulate 750 picoseconds (10 ** -12 seconds) of interaction between the VDR and Olmesartan.
I have also studied 25-D and 1,25-D but it is Olmesartan that the naysayers have focused upon, so today we will declare - game over - Olmesartan activates the VDR so that it can bind to the transcription coactivators, and transcribe genes from the DNA.
The Olmesartan molecule is just to the right of center of the image, in the background. Don't bother too much about the stick and ball amino acids at the lower front of the image - they are very important for reasons too complex to describe here The structure of the VDR is represented by the yellowy spiral backbones.
Brownian motion is a pseudo-random motion. These molecules are moving under inter-atomic forces, in a very regular manner. So 'Brownian' would not be a good description,in fact
well, the molecule is in a box, to give a finite size to the simulation, and the box is filled with water molecules (about 5000 of them), so there is quite a lot of 'traffic' to stay clear of...
So some 5,000 molecules banging around in some 750,000 femtoseconds, plus vanderwalls forces, covalent bonds; that sounds like a HUGE simulation. What kind of machine did you run it on?
I watched the RAM version. My engineer's heart loves it. But when does the docking occur? Is it already accomplished when the video starts?
john
____________________ RA 125D38, MP 9/05 Ph2 12/05 Ph3 09/06, Oct07 2510, NoIRs lite exp r/t work covered up
John,
The docking trajectory is problemmatic right now, as the entire field of biology is working with a VDR model (PDB:1DB1) which is genetically engineered to have amino acids missing from a critical region (residues 164-216) of the VDR. The region through which the ligand most likely enters the VDR I can get around this later by "growing" the VDR using MD, but first I have to learn to crawl, then walk
For this simulation, the benicar was tacked onto the VDR, so the software manipulates them as a single molecule (there's generalized software for you). It was placed into the optimum position obtained with Autodock. The 5004 water molecules were added, then the shebang was energy optimized, then the water was allowed to 'soak' into the receptor for a few picoseconds, and then the simulation begins. Actually, there are only an avg 2.5 hydrogen bonds at the very start, and the receptor/ligand complex bound themselves together over the first 600 picoseconds, or so, to a final average of about 7 hbonds, as the Olmesartan and VDR figured out the best orientation and position to nestle into. I have plotted the graphs of this trend, and will no doubt put them in some presentation, sooner or later
I put together the computer system from a motherboard/CPU combination at FRY's, overclocked from 1800 MHz to 3000 MHz (the new E4300 is an overclocker's delight). I upgraded the motherboard when I found this was running twice as fast as my (2005 model) Opteron-based system
Operating system is Linux, Fedora core 6, everything is command-line driven (none of this silly GUI stuff)
This weekend I am going to finish off putting together a small 3-machine cluster, which should give me about 5 times the speed I am getting now (cut from 10 hour runs to 2 hours)..
As per movement, I find it interesting that "in silico" is often described with "crystal structure" term which seems to imply a rigid form that is different from a plastic-pliable dance. Even "docking" sounds less organic or flowing.
But the structures move, and twist. I like that concept even when I've seen the videos when Dr Marshall has flipped them around to show different angles than the typical chemical compound 2-D structures you might find in a Wikipedia description. Made sense on the Science DVD label that way too, suggesting there was more than one way to see these. Clearly video is critical in describing the science.
I always see DNA as having to be a moving event else it wouldn't have the spiral shape. Even look at how they relate within the spiral structures. A logic for movement seems evident.--JRF
My Doc won't look at this ...Maybe, if Dr.Sharma or the Americam Thoractic Society "gets it" I'll get Beni Q6H as I requested... what I got today was -The Doctor says if your herxheimer reaction gets severe, you should give us a call and we'll see what we can do. bunk.
CONGRATS Trevor. Thank you for all your incredible work.
____________________ Saroidosis/lungs, 25D7 (8/07) Spireva,Ibuprofen, NoIRs, lite exp r/t work
Nice to see somebody from Wrozlaw be as fascinated as I am by Trevor's pathbreaking work!
Evelin
PS: My mother was born in Wrozlaw and in September I plan to visit it with my parents for the first time!
What is the underlying molecular basis behind the fact that olmesartan activates the VDR in a more controllable manner than vitamin D 1,25? Or is this based on clinical experience? What are the limits of molecular modelling in estimating an agonist's effect on a receptor?
____________________ CFS/ME, stopped olmesartan March 2014, feeling quite well, but not 100 %
Inge,
The affinity for the VDR of Benicar is low. That's why we need to use a higher concentration.
Although Benicar closes off the Angiotensin II Receptor (AT2R) at below 20mg/day, we need a much higher dose to properly activate the VDR. Thus the displacement of ligands from the VDR is easier to control by dosage than its blockade of the AT2R.
A really high affinity VDR ligand, like the ANTAGONIST Telmisartan (which you don't want to take under any circumstances) only requires a fraction of a tablet to block the action of multiple Benicar tablets for 24 hours or so...
Much worse than suppressing the immune system, as the VDR also transcribes Cancer metastasis suppressing proteins, and other very important bodily functions as well
Luckily, it isn't a very popular ARB And they only take it once a day, which is not frequent enough to completely block VDR transcription.
I have been busy working on firming up the final bits of the Marshall Pathogenesis - the bits that the skeptics still point fingers at
