Exhaustiveness/Binding affinity

[gtzotzos]

Hi everybody,

I'm dealing with two transporter proteins binding aliphatic ligands. The ligands are very flexible with anything up to 13 C-C rotating bonds. I am trying to find out whether the two proteins have the ability to discriminate the various ligands. I assume that such discrimination should manifest itself in terms of binding affinity.

The observations below give rise to a number of questions and I'd be grateful for any suggestions/answers:

1. Repeating the docking at the same exhaustiveness produces different energy minima (± 0.4 kcal/mol). If this is to be expected, then I would assume that increasing the exhaustiveness should result in minima closer to the absolute minimum. This is not the case. In the attachment exhaustiveness of 240 (log_ex240.txt) generates a lower minimum than exhaustiveness 400(log_ex400.txt). Any explanation for this?

2. Would binding affinity be measured in terms of the minimum energy reached or it'd be best to measure it as the average binding affinities of all models generated by VINA?

3. Are there any theoretical limitation is trying to compare binding affinities between homologous proteins to the same ligands?

Thanks in advance

George

Exhaustiveness: 240

mode | affinity | dist from best mode
| (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
1 -7.6 0.000 0.000
2 -7.6 1.108 1.447
3 -7.6 1.737 3.947
4 -7.5 2.325 5.187
5 -7.5 1.566 3.528
6 -7.5 2.101 4.808
7 -7.5 1.142 2.439
8 -7.5 1.202 1.812
9 -7.3 4.061 8.577
Writing output ... done.
================

Exhaustiveness: 400

mode | affinity | dist from best mode
| (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
1 -7.4 0.000 0.000
2 -7.4 2.476 5.237
3 -7.4 1.797 4.026
4 -7.4 1.554 4.197
5 -7.4 1.423 4.294
6 -7.4 2.449 5.302
7 -7.3 2.146 5.042
8 -7.3 2.175 5.399
9 -7.2 2.399 5.038
Writing output ... done.

[oleg_trott]

1. Repeating the docking at the same exhaustiveness produces different energy minima (± 0.4 kcal/mol). If this is to be expected, then I would assume that increasing the exhaustiveness should result in minima closer to the absolute minimum. This is not the case. In the attachment exhaustiveness of 240 (log_ex240.txt) generates a lower minimum than exhaustiveness 400(log_ex400.txt). Any explanation for this?

Yes. The docking optimizes the total score, while only its intermolecular part is used in predicting the binding affinity (see the paper) Still, your results seem very unusual to me. I can't tell you more, because I obviously don't have all the information about your case.

[gtzotzos]

Hi Oleg,

Indeed, the results are strange. I'm attaching the input files just in case you have the time to check them out.

Many thanks

George

PS. The config is as follows:

receptor = protein.pdbqt
ligand = 16COOH.pdbqt

center_x = 7.057
center_y = -4.02
center_z = 15.831

size_x = 24
size_y = 20
size_z =24

exhaustiveness = 240

[gtzotzos]

Hi again,

I don't wish to load the system with the same question but, for the type of ligand that I use, it seems that increasing the exhaustiveness quite often results in lower binding affinities (WEIRD !!!).

The results are below. Question: Can any conclusions be drawn from the rmsd values?

Sorry to persist on this but deriving binding affinities from docking for this type of ligand may be futile. Any suggestions would be most welcome. Thanks in advance

George


PS. Here's a different example to the one I posted yesterday.

conf.txt

receptor = 1dqe.pdbqt
ligand = bomAc.pdbqt

center_x = 3.541
center_y = 29.76
center_z = 0.768

size_x = 18
size_y = 18
size_z =18

exhaustiveness = 400

EXHAUSTIVENESS: 80

mode | affinity | dist from best mode
| (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
1 -8.0 0.000 0.000
2 -7.9 2.828 5.859
3 -7.9 2.759 6.534
4 -7.8 2.718 5.926
5 -7.8 2.316 6.190
6 -7.8 4.243 7.677
7 -7.8 2.645 6.166
8 -7.8 2.325 4.943
9 -7.8 2.552 5.649

EXHAUSTIVENESS: 240

mode | affinity | dist from best mode
| (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
1 -8.0 0.000 0.000
2 -7.9 2.859 5.789
3 -7.9 2.068 4.988
4 -7.9 2.556 6.004
5 -7.9 2.951 6.397
6 -7.9 2.540 5.363
7 -7.8 2.814 5.676
8 -7.8 2.502 5.434
9 -7.8 2.663 6.547

EXHAUSTIVENESS: 400

mode | affinity | dist from best mode
| (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
1 -7.7 0.000 0.000
2 -7.6 2.950 6.312
3 -7.5 1.748 4.703
4 -7.5 2.020 4.839
5 -7.5 2.793 6.339
6 -7.4 1.283 1.864
7 -7.4 2.966 5.370
8 -7.4 2.745 5.314
9 -7.4 2.410 3.485