Hi all,
I performed totally of +1 us Accelerated MD (aMD) of ERa starting from the "Apo" structure (pdb id:1a52) such as many before me. However, the aMD approach speed-up the simulations around 1500x compared to the classical MD, thus to the sub-milliseconds range. I tried various initial conditions (with and without Agonist and/or Antagonist and/or co-activator peptide and etc.), however I was not able to reproduce the X-ray H12 conformation close to agonist or antagonist form. In fact, all previous simulations achieved the same results...To my best knowledge it is unknown the sequence of the structural changes and in particular how H12 adopts it known conformation.
Remarkably, my results shown that ERa H12 switches from "Apo" to Agonist or even Antagonist conformation ONLY after dimmer formation i.e. when I used dimmer complex as a starting point. Such simulation wasn't performed before due to computational cost and I am not able to compare my results to some previous studies.
I was wondering whether this is possible from the experimental point of view? How it would sounds for a specialist in this area that not work in the filed of MD simulations? Any comments are welcome!
Thanks in advance!
P.S. You can see some video and pictures here:
http://www.youtube.com/watch?v=X0O7WtPC-xk
http://www.youtube.com/watch?v=IICyVUErbis&feature=youtu.be
https://www.researchgate.net/publication/233988449_Agonist_Comparison_dimer
https://www.researchgate.net/publication/233988465_Antagonist_Comparison_dimer
Data ERdimer
Data Agonist_Comparison_dimer
Data Antagonist_Comparison_dimer
Hi friends,
Most of the additional MD runs confirmed our previous results. I performed also PCA and correlation analysis and it seems that from computational point of view everything looks fine. In fact for me was a big surprise that I obtained so good overlap between MD generated and agonist X-ray structure:
https://www.researchgate.net/publication/234051774_Apo_to_Agonist._Comparison_with_X-ray
Here is the path:
http://www.youtube.com/watch?v=IICyVUErbis&feature=youtu.be
However, I still wonder how the "dimer hypothesis" about H12 conformation will be accepted from the nuclear receptors community. Any positive or negative comments are really welcome!
Data Apo_to_Agonist. Comparison_with_X-ray
Finally I was able to write the manuscript, which can be found here: https://www.researchgate.net/publication/236342591_Helix_12_orientation_in_Estrogen_receptor_is_mediated_by_receptor_dimerization_evidence_from_molecular_dynamics_simulations
However, It is always a pity to receive a review in three sentences: " Even if the idea of the dimerization as key factor for ER H12 orientation could be a fascinating idea, it should be demonstrated by experimental data not only by MD simulations. There are no evidences more than the MD simulations presented by the author." Ok just do it :) It is also not correct to attack other authors via review. God job JCIM! :)
From computational point of view when 6 of 9 independent aMD simulations show the same behaviour and reproduce the well known helix12 states only in dimer but not in monomer (10 of 10) this deserves to be explained.
Article Helix 12 orientation in Estrogen receptor is mediated by rec...
Its valuable results... I read your article and I compared your results with my work
I have run 100 ns normal MD simulation for both dimer and monomer 1A52..with or without ligand (New designed).. and I did not got any agonist or antagonist H12 pathway for dimer/monomer alone, it was just swing up during simulation..while the dimer complex I was found new behavior of H12 (the two H12 in the dimer interact with each other during 100 ns).. I am just try to analyze this behave..especially that the MD of dimer alone without complex (both H12 moved far from each other to the binding site as usual).
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