<p>It is best to contextualise the numbers. -1 kcal/mol is about the potential energy gained from a hydrogen bond —technically described in the r^6 part of the Lenard–Jones term, it is also the average collision energy of a water molecule at 37°C as that is RT (<span class="math-container">$\frac{k_b\cdot T}{N_A}$</span>, <a href="https://en.wikipedia.org/wiki/KT_(energy)" rel="nofollow noreferrer">wiki</a>)under a <a href="https://en.wikipedia.org/wiki/Maxwell%E2%80%93Boltzmann_distribution" rel="nofollow noreferrer">Maxwell–Boltzmann distribution</a>. A salt bridge –2 kcal/mol (Columbic force term).
So your scores are not very low, hence why you are counting two hydrogen bonds. Although you can also see a lovely sulfur-pi interaction which is –1 to –2 kcal/mol, so those bonds alone are probably making a –4 kcal/mol contribution, so I am guessing that some terms may be horrendous, such as repulsion forces etc.
A nice metric is doing a conversion to <a href="https://en.wikipedia.org/wiki/Ligand_efficiency" rel="nofollow noreferrer">ligand efficiency</a>, which weeds out affinities driven by size of the molecule... in this case most of the molecule is doing nothing.
Also, most programs have an accuracy of 1 kcal/mol or higher.</p>
<p>So one cannot say what ∆∆G is the best with the data at hand due to noise, but one can say that the ∆∆G is not low enough... Sorry.</p>

CC BY-SA 4.0
2021-06-14T00:08:10.003Z
Thanks. By ` ∆∆G` Do you mean ` affinity (kcal/mol)`?
Then what do you consider ideal score range for  ∆∆G. Since you said that my score above is not low enough?
littleworth
CC BY-SA 4.0
2021-06-14T16:13:36.543Z
I did and it generally is fine, but variations of definitions and calculation come into play. Gibbs free energy is `∆G` (so one delta to start with), although some tools refer to `∆G_bind` as ∆∆G, and generally it's intended as `∆∆G = ∆G_holo - (∆G_apo + ∆G_aq)`, where `∆G_aq` is the free energy in aqueous solvent, but this is not always true as there may be fancy stuff correcting for ∆G_aq (which makes little sense for a high partition coefficient compound), Vina is one of them.
Matteo Ferla
CC BY-SA 4.0
2021-06-14T16:17:05.607Z
Higher than 10 kcal/mol... If you calculate the ligand efficiency it will be something between –0.1 and –0.2 kcal/mol/heavy. If your ligand is meant to dock with a high affinity, then I would revisit the template —a holo enzyme structure with the substrate removed is best, check the protonation of that aspartate etc.
Matteo Ferla
CC BY-SA 4.0
2021-06-14T16:19:44.100Z
Ah. I just noticed your box is giving a warning of being over 30 Å x 30 Å x 30 Å. Which is huge.
Matteo Ferla
CC BY-SA 4.0
2021-06-20T10:24:11.417Z
when you said `10 kcal/mol`, how did you come up with that number?
Any reference/publication for that?
littleworth
CC BY-SA 4.0
2021-06-20T22:08:38.600Z
It's a ballpark figure. Playing devil's advocate, if you take the example of aspirin (an old small drug that's totally non-specific, that is taken at a 1,000 mg dose, that is charged, that is quickly broken by a liver cytochrome etc), it's binding to it's target is only -7 kcal/mol, which for 13 heavy atoms makes it's LE -0.5 kcal/mol, meaning that threshold doesn't always hold true (with massive caveats)
Matteo Ferla
CC BY-SA 4.0
2021-06-13T18:41:09.387Z
2021-06-13T18:41:09.387Z
Matteo Ferla
<p>I have perform a ligand-protein docking using <a href="http://vina.scripps.edu" rel="nofollow noreferrer"><strong>Autodock Vina</strong></a>.
The result of the docking looks like this:</p>
<pre><code>WARNING: The search space volume &gt; 27000 Angstrom^3 (See FAQ)
Detected 8 CPUs
Reading input ... done.
Setting up the scoring function ... done.
Analyzing the binding site ... done.
Using random seed: -1553787135
Performing search ... done.
Refining results ... done.

mode |   affinity | dist from best mode
     | (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
   1         -5.9      0.000      0.000.  Pose 1
   2         -5.7     22.945     25.492.  Pose 2
   3         -5.5      1.426      2.046.  Pose 3
   4         -5.5     23.669     25.616
   5         -5.4     25.783     29.152.  .....
   6         -5.3     21.146     23.357
   7         -5.2     20.323     22.545
   8         -5.2     23.864     26.064
   9         -5.1     23.422     26.585.  Pose 9
</code></pre>
<p>As far as I understand from these statistics Mode 1(Pose 1) is the best.
However when I actually visualize them in Pymol, Pose 1 has no hydrogen bonding at all
but Pose 2 has.</p>
<p>My question is how can we judge if which of those two Pose is the best to use?</p>
<p>Note in figure below Pose 2 has dashed line (Hydrogen bond).</p>
<p><a href="https://i.sstatic.net/8gY6p.jpg" rel="nofollow noreferrer"><img src="https://i.sstatic.net/8gY6p.jpg" alt="enter image description here" /></a></p>

<protein-structure><docking><structural-biology>
How to tell if our ligand-protein docking is good from AutoDock Vina's result
# How to tell if our ligand-protein docking is good from AutoDock Vina's result

(Asked by: username_0 on 2021-06-12)

I have perform a ligand-protein docking using Autodock Vina.
The result of the docking looks like this:
WARNING: The search space volume > 27000 Angstrom^3 (See FAQ)
Detected 8 CPUs
Reading input ... done.
Setting up the scoring function ... done.
Analyzing the binding site ... done.
Using random seed: -1553787135
Performing search ... done.
Refining results ... done.

mode |   affinity | dist from best mode
     | (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
   1         -5.9      0.000      0.000.  Pose 1
   2         -5.7     22.945     25.492.  Pose 2
   3         -5.5      1.426      2.046.  Pose 3
   4         -5.5     23.669     25.616
   5         -5.4     25.783     29.152.  .....
   6         -5.3     21.146     23.357
   7         -5.2     20.323     22.545
   8         -5.2     23.864     26.064
   9         -5.1     23.422     26.585.  Pose 9

As far as I understand from these statistics Mode 1(Pose 1) is the best.
However when I actually visualize them in Pymol, Pose 1 has no hydrogen bonding at all
but Pose 2 has.
My question is how can we judge if which of those two Pose is the best to use?
Note in figure below Pose 2 has dashed line (Hydrogen bond).

**Tags:** protein-structure, docking, structural-biology

---

## 1 answers

### Answer by username_1 on 2021-06-13. Score: 2

It is best to contextualise the numbers. -1 kcal/mol is about the potential energy gained from a hydrogen bond —technically described in the r^6 part of the Lenard–Jones term, it is also the average collision energy of a water molecule at 37°C as that is RT ($\frac{k\_b\cdot T}{N\_A}$, [wiki](https://en.wikipedia.org/wiki/KT_(energy)))under a [Maxwell–Boltzmann distribution](https://en.wikipedia.org/wiki/Maxwell%E2%80%93Boltzmann_distribution). A salt bridge –2 kcal/mol (Columbic force term).
So your scores are not very low, hence why you are counting two hydrogen bonds. Although you can also see a lovely sulfur-pi interaction which is –1 to –2 kcal/mol, so those bonds alone are probably making a –4 kcal/mol contribution, so I am guessing that some terms may be horrendous, such as repulsion forces etc.
A nice metric is doing a conversion to [ligand efficiency](https://en.wikipedia.org/wiki/Ligand_efficiency), which weeds out affinities driven by size of the molecule... in this case most of the molecule is doing nothing.
Also, most programs have an accuracy of 1 kcal/mol or higher.

So one cannot say what ∆∆G is the best with the data at hand due to noise, but one can say that the ∆∆G is not low enough... Sorry.

> **Comments:**
> **username_0**: Thanks. By ` ∆∆G` Do you mean ` affinity (kcal/mol)`? Then what do you consider ideal score range for  ∆∆G. Since you said that my score above is not low enough?  
> **username_1**: I did and it generally is fine, but variations of definitions and calculation come into play. Gibbs free energy is `∆G` (so one delta to start with), although some tools refer to `∆G_bind` as ∆∆G, and generally it's intended as `∆∆G = ∆G_holo - (∆G_apo + ∆G_aq)`, where `∆G_aq` is the free energy in aqueous solvent, but this is not always true as there may be fancy stuff correcting for ∆G_aq (which makes little sense for a high partition coefficient compound), Vina is one of them.  
> **username_1**: Higher than 10 kcal/mol... If you calculate the ligand efficiency it will be something between –0.1 and –0.2 kcal/mol/heavy. If your ligand is meant to dock with a high affinity, then I would revisit the template —a holo enzyme structure with the substrate removed is best, check the protonation of that aspartate etc.  
> **username_1**: Ah. I just noticed your box is giving a warning of being over 30 Å x 30 Å x 30 Å. Which is huge.  
> **username_0**: when you said `10 kcal/mol`, how did you come up with that number? Any reference/publication for that?  
> **username_1**: It's a ballpark figure. Playing devil's advocate, if you take the example of aspirin (an old small drug that's totally non-specific, that is taken at a 1,000 mg dose, that is charged, that is quickly broken by a liver cytochrome etc), it's binding to it's target is only -7 kcal/mol, which for 13 heavy atoms makes it's LE -0.5 kcal/mol, meaning that threshold doesn't always hold true (with massive caveats)  

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