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PostPosted: Wed Oct 21, 2009 7:35 am 
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Hi all
I used autodock vina and found that, when I allow the flexibility in the 4 residues (arg,trp and glu) at the binding site, the affinity (Free energy of binding ??) for the same carbohydrate molecule falls down about 1/2 (from -6.2 (rigid receptor) to -3.4 (flexible aa in receptor)). If i allow the flexibility in only 1 amino acid then it doesn't goes down so much (abt 5kcal/mil). Docked structure is the same as it was in the case when the receptor was rigid or 1 aa flex. I will be happy to know the reason that why affinity decreases when the flexibility in residues of receptor is being allowed ??
Thanking u
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PostPosted: Wed Oct 21, 2009 4:32 pm 
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sushilbioinfo wrote:
Docked structure is the same as it was in the case when the receptor was rigid or 1 aa flex.


If the docked structure is exactly the same, the predicted binding affinity should be exactly the same as well. If you are seeing otherwise, please make sure you are right, and provide some evidence (all relevant files) and a reproducible case.

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PostPosted: Thu Nov 26, 2009 8:34 am 
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Hi,
I didnt wrote exact same, but its almost same. I am facing 1 more issue which is also related to side chain flexibility. When I allow the flexibility in one TRP residue with 3 other residues in the binding site, AutoDock Vina flips the two rings of TRP by 180 degree and energy falls by about 2 Kcal/mol. But when I allow the flexibility in only 3 residues ( TRP is rigid this time) binding affinity is more. So my question is that, if the side chain rotation of TRP residue is decreasing the Binding affinity then, why optimization procedure accepting that change ? In my opinion if any change in the confirmation is lowering the binding energy then it shuld be rejected ( with certain criterion so that we can avoid trapping in local minima ). What is the reason behind such type of movement in during side chain flexibility ??


Last edited by sushilbioinfo on Fri Dec 04, 2009 1:59 pm, edited 1 time in total.

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PostPosted: Thu Nov 26, 2009 5:50 pm 
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I believe this issue is this... You believe that it is vina's objective to find the conformation where your drug binds the best. I do not believe this is true, instead vina's objective is to fine the best overall conformation regardless of how much your drug binds. then when this is found it evaluates how well your drug binds...it just so happens that by allowing your receptor to be flexible it is finding a lower overall energy and in this new conformation your drug does not bind as well.


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PostPosted: Fri Dec 11, 2009 7:20 am 
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I had exactly the same issue. I wanted to compare dockings of a ligand with Autodock 4.0 and Autodock vina: I obtained better energy results and a positioning of the ligand comparable to the one obtained in the greater cluster of Autodock4.0 with Vina when I used a rigid structure of my protein, but when I add flexible residues, the same with both softwares, energy of binding is about -17 kcal/mol with autodock 4.0 and about -5 kcal/mol with Vina! I checked the gridbox, augmented its side, all flexible residues being completely in it... but still the same result. :?
On the other hand, the resulting conformation of the ligand seems to be very close to the one obtained with autodock 4.0.


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PostPosted: Sun Dec 13, 2009 11:45 pm 
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sushilbioinfo wrote:
Hi,
I didnt wrote exact same, but its almost same. I am facing 1 more issue which is also related to side chain flexibility. When I allow the flexibility in one TRP residue with 3 other residues in the binding site, AutoDock Vina flips the two rings of TRP by 180 degree and energy falls by about 2 Kcal/mol. But when I allow the flexibility in only 3 residues ( TRP is rigid this time) binding affinity is more. So my question is that, if the side chain rotation of TRP residue is decreasing the Binding affinity then, why optimization procedure accepting that change ? In my opinion if any change in the confirmation is lowering the binding energy then it shuld be rejected ( with certain criterion so that we can avoid trapping in local minima ).


You are mistaken here. Only intermolecular interactions are counted in estimating the ligand binding energy (for the best binding mode) in Vina, however, intramolecular terms contribute to the predicted binding modes. So, if a residue is "strained", according to the scoring function, by releasing it, you may "inconvenience" the ligand, lowering its predicted binding affinity. I had explained this before in this forum.

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