Protein Design Critique: IL-7R Binder Redesign

Started by bcov

Bruno Kestemont Lv 1

Hopefully, the AA information on the Wiki (for Lua scripting) is still correct:

https://foldit.fandom.com/wiki/Lua_Script_Library#fsl.Aminos_–_A_table_of_useful_information_about_the_residues.

It gives the following information about any aminoacid:
{short, abbrev, longname, hydro, scale, pref, mol wt, isoelectric point (pl), van der waals volume, abbrevcap, codon}

abrev is used to call or recognize the AA in the Lua functions
abbrevcap is used in the residues info (clicking on Tab on a residue)
longname is the AA name
hydro gives the preferred hydrophobicity
pref gives the preferred secundary structure

It's used in several mutate recipes like
Mutate No Wiggle
Maaa

Additionally, Jeff101 collected additional info from the literature. I used it in the Maaa recipe (probabilistic options). Here is a copy of (an extract from) Jeff"s library.

–Library of Amino Acid properties by jeff101 (Foldit player)
–v1 22 Jan 2016
—————————————————————–
–START Library of Amino Acid properties by jeff101
–Free for non commercial use providing the source is aknowledged
–Source: jeff101 (Copyright) based on the following sources:
– L75=Biochemistry by Lehninger 2nd Ed 1975 ISBN=0-87901-047-9
– from Sigma 1998 catalog
– JJR Frausto da Silva and RJP Williams' The Biological Chemistry of the Elements ISBN=0-19-855802-3
– L&B=SJ Lippard and JM Berg's Principles of Bioinorganic Chemistry ISBN=0-935702-73-3
– Alberts' Molecular Biology of the Cell ISBN=0-8240-3695-6
– CRC 1980-1 61st Edition
– C&SI=Cantor & Schimmel's Biophysical Chemistry Part I: The conformation of biological macromolecules ISBN=0-7167-1188-5
– B&T=Branden & Tooze's Introduction to Protein Structure ISBN=0-8153-0270-3
– Stryer=Lubert Stryer's Biochemistry 4th Edition ISBN=0-7167-2009-4
–
– LUA transposed by Bruno Kestemont
–USE: All the AAs and properties are in the same order
–Copy-paste the properties you need in your recipes, comment the other ones in order to avoid duplications of names.
–EXTRACT this only an extract for Maaa
AAshort ={'a','c','d','e','f','g','h','i','k','l','m','n','p','q','r','s','t','v','w','y'} –
AAname ={'Alanine','Cysteine','Aspartic Acid','Glutamic Acid','Phenylalanine','Glycine','Histidine','Isoleucine','Lysine','Leucine','Methionine','Asparagine','Proline','Glutamine','Arginine','Serine','Threonine','Valine','Tryptophan','Tyrosine'} –p.73 L75

FreqInProt ={8.3,1.7,5.3,6.2,3.9,7.2,2.2,5.2,5.7,9,2.4,4.4,5.1,4,5.7,6.9,5.8,6.6,1.3,3.2} –frequency in proteins (%)
VolumeVDW ={67,86,91,109,135,48,118,124,135,124,124,96,90,114,148,73,93,105,163,141} –VDW volume in cubic A
Pa ={1.41,0.66,0.99,1.59,1.16,0.43,1.05,1.09,1.23,1.34,1.3,0.76,0.34,1.27,1.21,0.57,0.76,0.9,1.02,0.74} –Pa=a-helix preference
Pb ={0.72,1.4,0.39,0.52,1.33,0.58,0.8,1.67,0.69,1.22,1.14,0.48,0.31,0.98,0.84,0.96,1.17,1.87,1.35,1.45} –Pb=b-strand preference
Pt ={0.82,0.54,1.24,1.01,0.59,1.77,0.81,0.47,1.07,0.57,0.52,1.34,1.32,0.84,0.9,1.22,0.9,0.41,0.65,0.76} –Pt=reverse turn preference

fa ={0.522,0.278,0.351,0.549,0.402,0.19,0.446,0.358,0.383,0.48,0.429,0.263,0.212,0.421,0.282,0.282,0.295,0.409,0.409,0.22} –fa=freq helical
fb ={0.167,0.222,0.137,0.044,0.219,0.138,0.122,0.274,0.126,0.209,0.286,0.113,0.106,0.211,0.154,0.124,0.205,0.282,0.203,0.22} –fb=freq beta

Hfreq ={1.29,1.11,1.04,1.44,1.07,0.56,1.22,0.97,1.23,1.3,1.47,0.9,0.52,1.27,0.96,0.82,0.82,0.91,0.99,0.72} –alpha-helix frequency
Sfreq ={0.9,0.74,0.72,0.75,1.32,0.92,1.08,1.45,0.77,1.02,0.97,0.76,0.64,0.8,0.99,0.95,1.21,1.49,1.14,1.25} –beta-sheet frequency
Lfreq ={0.78,0.8,1.41,1,0.58,1.64,0.69,0.51,0.96,0.59,0.39,1.28,1.91,0.97,0.88,1.33,1.03,0.47,0.75,1.05} –beta-turn frequency
–END Amino Acid properties by jeff101 (EXTRACT)

bkoep Staff Lv 1

If two regions of a protein interact strongly enough, then you can sometimes insert an unstructured loop between them and they will still fold together. However, this usually works best if each of the regions can fold okay on its own (as an independent, well-folded domain). If the regions are small and poorly-folded on their own, then the unstructured loop is more likely to confound folding.

For some protein design projects, we need to fuse two protein domains together as a single chain, but we don't want to engineer a structured loop between them. In this case, we'll connect them with a "GS-linker" which is just a long stretch of alternating GLY and SER residues (GLY is very flexible and tends to be unstructured; SER is polar and helps to keep the linker soluble).

Rosetta (the modeling software underlying Foldit) is not very well suited for modeling disordered loops. Rosetta is pretty good about evaluating the energy of a single, rigid state, but people tend to prefer molecular dynamics simulations to model flexible or dynamic regions of a protein.

Also, disordered loops are generally less useful for designed proteins, where we are mostly interested in precise control over the entire shape of the protein. It's true that a lot of natural proteins have disordered loops and that these loops can be essential for natural protein functions; but the exact role of a dynamic loop is very difficult to study, much less to design for. In Foldit we strongly discourage players from designing long unstructured loops, because they confer little—if any—benefit, and they are very likely to disrupt folding.