TY - JOUR
T1 - Minimal ensembles of side chain conformers for modeling protein-protein interactions
AU - Beglov, Dmitri
AU - Hall, David R.
AU - Brenke, Ryan
AU - Shapovalov, Maxim V.
AU - Dunbrack, Roland L.
AU - Kozakov, Dima
AU - Vajda, Sandor
PY - 2012/2
Y1 - 2012/2
N2 - The goal of this article is to reduce the complexity of the side chain search within docking problems. We apply six methods of generating side chain conformers to unbound protein structures and determine their ability of obtaining the bound conformation in small ensembles of conformers. Methods are evaluated in terms of the positions of side chain end groups. Results for 68 protein complexes yield two important observations. First, the end-group positions change less than 1 Å on association for over 60% of interface side chains. Thus, the unbound protein structure carries substantial information about the side chains in the bound state, and the inclusion of the unbound conformation into the ensemble of conformers is very beneficial. Second, considering each surface side chain separately in its protein environment, small ensembles of low-energy states include the bound conformation for a large fraction of side chains. In particular, the ensemble consisting of the unbound conformation and the two highest probability predicted conformers includes the bound conformer with an accuracy of 1 Å for 78% of interface side chains. As more than 60% of the interface side chains have only one conformer and many others only a few, these ensembles of low-energy states substantially reduce the complexity of side chain search in docking problems. This approach was already used for finding pockets in protein-protein interfaces that can bind small molecules to potentially disrupt protein-protein interactions. Side-chain search with the reduced search space will also be incorporated into protein docking algorithms.
AB - The goal of this article is to reduce the complexity of the side chain search within docking problems. We apply six methods of generating side chain conformers to unbound protein structures and determine their ability of obtaining the bound conformation in small ensembles of conformers. Methods are evaluated in terms of the positions of side chain end groups. Results for 68 protein complexes yield two important observations. First, the end-group positions change less than 1 Å on association for over 60% of interface side chains. Thus, the unbound protein structure carries substantial information about the side chains in the bound state, and the inclusion of the unbound conformation into the ensemble of conformers is very beneficial. Second, considering each surface side chain separately in its protein environment, small ensembles of low-energy states include the bound conformation for a large fraction of side chains. In particular, the ensemble consisting of the unbound conformation and the two highest probability predicted conformers includes the bound conformer with an accuracy of 1 Å for 78% of interface side chains. As more than 60% of the interface side chains have only one conformer and many others only a few, these ensembles of low-energy states substantially reduce the complexity of side chain search in docking problems. This approach was already used for finding pockets in protein-protein interfaces that can bind small molecules to potentially disrupt protein-protein interactions. Side-chain search with the reduced search space will also be incorporated into protein docking algorithms.
KW - Pre existing ensemble of conformers
KW - Protein binding
KW - Rotamer libraries
KW - Side chain flexibility
KW - Structure prediction
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U2 - 10.1002/prot.23222
DO - 10.1002/prot.23222
M3 - Article
C2 - 22105850
SN - 0887-3585
VL - 80
SP - 591
EP - 601
JO - Proteins: Structure, Function and Bioinformatics
JF - Proteins: Structure, Function and Bioinformatics
IS - 2
ER -