Foldit drug design introduction
My name is Steven Combs (aka free_radical). I am currently a post doc with a dual appointment at Vanderbilt University and Eli Lilly. I have been working with David Baker’s lab and the developers of Foldit to enable drug design in Foldit.
During one of the developers chats, it was mentioned that players wanted more updates on new developments in Foldit. I will try and update everyone as much as possible on my progress for drug design in Foldit and explain some of the scientific ideas behind the implementations in the game.
To start off, I would like to explain one component that has changed in Rosetta (the underlying software for Foldit) to enable drug design. Rosetta assigns properties to atoms based on the type of atom. These properties can be anything from whether the atom is a hydrogen bond donor/acceptor to whether the atom likes to be exposed to water or not. Further, numerical values used in scoring a residue based on its atoms can be assigned. Many of these values used in scoring are derived from the CHARMM force field, which was developed by Dr. Karplus (who just recently received a Nobel Prize in chemistry!).
While these values help with scoring the residue and atoms, they do little to tell about the configuration of the atom in relationship to other atoms bonded to it. This is extremely important in drug design. For drug design, the type of bonds that can be added or deleted or the types atoms that can be added or deleted need to know what the configuration of the original atom was. For example, if an atom is double bonded to another atom, can that atom form a triple bond? Does it have any free electrons to participate in another interaction? When building small-molecules for drug design, these properties, or chemical rules, need to be known.
To do this, I, along with members from the Meiler lab, have worked to put new atom types into Rosetta. I will use the amino acid TYR as an example of the new atom types. Below is a diagram of TYR with some of the atoms labeled with their properties assigned by Rosetta using the old atom type scheme.
Several properties are encoded onto the atom, such as the carbon being aromatic and the oxygen being polar. These properties are very useful when scoring the side-chain, but we also need to add on a layer for encoding the configuration of the atom.
The rules that we use to encode the configuration are based on the geometrical configuration of the atoms in relationship to what is bonded to and the number of electrons in the bonds (referred to as Gasteiger atom types). For our TYR example, the aroC retains the same original properties, but we also now know its geometry.
The new atom type is C_TrTrTrPi. This means that the carbon has three bonds that are in the trigonal configuration. Trigonal configuration refers the VSEPR rules. The Pi at the end of the naming means that there is one pi-orbital in the system, occupied by one electron. That pi-orbital is free to interact with other hydrogens or other pi-orbitals to form a cation-pi interaction or pi-pi interaction, all which are important for drug design (more on this topic in the future). For the oxygen, it is now labeled O_Te2Te2TeTe. This means that there are two lone pairs in tetrahedral (sp3, Te2Te2) and two bonds in tetrahedral configuration (TeTe).
While amino acids will not see much use for these types of descriptors for drug design, small molecules will. For example, lets look at a cyano group, which is a common group used in drug design.
In the cyano group, the old Rosetta designation for the atom is aroC, but the configuration of that atom is much different than the aroC seen in TYR! If we were to modify the atom, how would we know the configuration of the bonds? This is where the power of the new atom type comes into play. With the new atom typing, we now know that the carbon is linear (the DiDi portion; Di=diganol/linear) and that it has two pi-orbitals (PiPi). This means if we add or replace atoms, we know exactly the placement for the new atoms and the type of interactions this atom can make.
While these modifications may seem small, they greatly enhance the ability of Rosetta for drug design. With the new atom types, we can combine/add/delete/modify residues and small molecules rapidly and with ease.
For the upcoming weeks, are there specific topics that you would like to be addressed? What would everyone like to hear about? If anyone has any questions on this subject, I will be more than glad to address them!( Posted by free_radical 83 1754 | Wed, 01/21/2015 - 17:41 | 11 comments )