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Recipe: DDG Calculatr 1.1.0
Created by donuts554 83 115
4.75
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Name: DDG Calculatr 1.1.0
ID: 103728
Created on: Tue, 07/21/2020 - 17:47
Updated on: Sat, 07/25/2020 - 06:44
Description:

This recipe calculates the DDG Binding Energy of the complex of the locked and unlocked segments of the binder design puzzle in kCal/mol (kilocalorie per mole) and e^2/Angstrom (elementary charge squared per angstrom). This recipe also calculates the three most attractive and repulsive amino acid pairs in the locked and unlocked segments.
The more negative the DDG score, the more likely your protein is to bind to the locked receptor. It is somewhat similar to and based on how DDG is formally calculated in Rosetta. Instead of the various Rosetta subscores, this recipe takes into consideration the potential energy of the complex of the two segments, as determined by the force between every pair of amino acids that have one on the unlocked segment, and one on the locked segment of the puzzle, as determined by Coulomb's inverse-square law. Note: This version of the recipe does not take Clashing or Hydrophobic hiding or voids into consideration, so it seems that it would be best to use the Foldit score for your protein in the case that your protein has many clashes or exposeds or voids. I recommend using this recipe with no clashes, few exposeds and a little amount of voids in the unlocked segment, and to have the unlocked segment close to the locked segment of the binder puzzle so that the score that it would give would be more accurate.



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Comments

Susume's picture
User offline. Last seen 11 hours 24 min ago. Offline
Joined: 10/02/2011
Interesting idea!

This is a really interesting idea! A couple of things you might want to consider for a future version: I notice you are dividing the charge product by the distance between charges, but Coulomb's law actually uses the square of the distance - this is important because the attractive or repulsive force decreases very rapidly with distance.

The structure.GetDistance function that foldit Lua provides gives you the distance between the alpha carbons. You might get better accuracy by locating the polar atoms themselves and adding a band between them, then asking for the length of the band. That would definitely make the recipe much slower, though. One way to limit the time increase would be to query alpha carbon distance first (which is quite fast), and only use a band to get a more accurate distance if the alpha carbon distance is below some threshold (close enough that the difference between alpha carbon distance and sidechain to sidechain distance is expected to be significant).

I hope you'll keep working on this!

jeff101's picture
User offline. Last seen 18 hours 36 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
1/r vs 1/r^2
Coulomb's law for the force between 2 charges does go 
as 1/r^2, where r is the distance between the 2 charges,
but the potential energy due to this force goes as 1/r.

The gravitational force between 2 masses also goes
as 1/r^2 while the gravitational potential energy
goes as 1/r. 

The equations for electrostatic force & potential energy
are very similar to the equations for gravitational force &
potential energy. One difference is that the electrostatic
ones go as the product of 2 charges while the gravitational
ones go as the product of 2 masses.

Because of these things, I think using 1/r when calculating
the Binding Energy DDG makes more sense than using 1/r^2.

https://en.wikipedia.org/wiki/Inverse-square_law#Electrostatics
https://en.wikipedia.org/wiki/Inverse-square_law#Gravitation
https://en.wikipedia.org/wiki/Gravitational_energy#Newtonian_mechanics
https://en.wikipedia.org/wiki/Electric_potential_energy#Electrostatic_potential_energy_of_one_point_charge
Susume's picture
User offline. Last seen 11 hours 24 min ago. Offline
Joined: 10/02/2011
Thanks!

Thanks Jeff, I did not know that.

jeff101's picture
User offline. Last seen 18 hours 36 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
1/r vs 1/r^2
More arguments favoring 1/r instead of 1/r^2 are below:

Electrostatic forces (which go as the product of 2 charges 
divided by r^2, the square of the distance between the 
charges) are vectors with both magnitude and direction. 
Being vectors in 3D space gives x y and z components in 
cartesian coordinates. This makes it more complicated to 
calculate the overall force on a single charge due to a 
group of nearby charges.

Electrostatic energy (which goes as the product of 2 charges
divided by r, the distance between the charges) is a scalar 
with no direction or x y z components to worry about. This
makes it easier to calculate the overall energy of a group
of nearby charges.
Susume's picture
User offline. Last seen 11 hours 24 min ago. Offline
Joined: 10/02/2011
Storing greatest contributors, and charges assigned to sidechain

I notice the recipe attempts to keep track of the top three pairs contributing to repulsion, and the top three pairs contributing to attraction. When a new pair exceeds the #1 spot in these lists, it gets inserted at the top of the list and the others are pushed down. However, if a new pair falls between #1 and #2, or between #2 and #3, it is not getting added into the list as it should.

The recipe is using the following values for the point charges (measured in e, elementary charge) for each amino acid:
0 a, c, f, g, i, l, m, p, v
1 k, w
3 r
-1 h, n, q, s, t, y
-2 d, e
I assume these are based on the number of polar atoms in the sidechain. D and E are commonly considered charged, while I guess the polar atoms on the others could be considered to have a partial charge. Is there a table somewhere of how charged the various amino acids are? On those that have both a partial positive and a partial negative, should these point charges be considered separately rather than aggregated?

Joined: 06/20/2019
Groups: Go Science
Thx for suggstions! There's a AA table & part charge is separate

I will try to fix the issue of when a new pair falls in between #1 & #2 or #2 & #3 in the next version of this recipe, and I will try to make the recipe more accurate by adding a band if the distance between the amino acids is below a threshold. Thank you for the suggestions!

I think there is a table somewhere on how charged the various amino acids are, at http://thinkpeptides.com/aminoacidproperties.html . On the table, it seems that the isoelectric point and sidechain acidity/basicity of each amino acid can show how charged the various amino acids are.

On the amino acids that have both a partial positive and a partial negative, I think the point charges should be considered separately rather than aggregated, because the partial charges do play a significant role in the binding mechanism of two proteins, as either of them can attract any charged amino acid. If they are aggregated, then those amino acids wouldn't be polar and their partial positive and negative charges wouldn't be taken into consideration.

I would like to point out that in this recipe, the amino acids h, n, q, s, t, and y are assigned either 1 or -1 elementary charge depending on the corresponding amino acid pair it is compared with, as both of the polar atoms can be bonded to.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, RosettaCommons