TY - JOUR
T1 - Conformer Selection and Induced Fit in Flexible Backbone Protein-Protein Docking Using Computational and NMR Ensembles
AU - Chaudhury, Sidhartha
AU - Gray, Jeffrey J.
N1 - Funding Information:
We acknowledge Michael Daily, Monica Berrondo, Arvind Sivasubramanian, and Chu Wang for insightful discussions and for reading and editing of the manuscript. This work was supported by National Institute of Health grant R01 GM078221. S.C. received funding from National Institute of Health training grant T32 GM008403.
PY - 2008/9/12
Y1 - 2008/9/12
N2 - Accommodating backbone flexibility continues to be the most difficult challenge in computational docking of protein-protein complexes. Towards that end, we simulate four distinct biophysical models of protein binding in RosettaDock, a multiscale Monte-Carlo-based algorithm that uses a quasi-kinetic search process to emulate the diffusional encounter of two proteins and to identify low-energy complexes. The four binding models are as follows: (1) key-lock (KL) model, using rigid-backbone docking; (2) conformer selection (CS) model, using a novel ensemble docking algorithm; (3) induced fit (IF) model, using energy-gradient-based backbone minimization; and (4) combined conformer selection/induced fit (CS/IF) model. Backbone flexibility was limited to the smaller partner of the complex, structural ensembles were generated using Rosetta refinement methods, and docking consisted of local perturbations around the complexed conformation using unbound component crystal structures for a set of 21 target complexes. The lowest-energy structure contained > 30% of the native residue-residue contacts for 9, 13, 13, and 14 targets for KL, CS, IF, and CS/IF docking, respectively. When applied to 15 targets using nuclear magnetic resonance ensembles of the smaller protein, the lowest-energy structure recovered at least 30% native residue contacts in 3, 8, 4, and 8 targets for KL, CS, IF, and CS/IF docking, respectively. CS/IF docking of the nuclear magnetic resonance ensemble performed equally well or better than KL docking with the unbound crystal structure in 10 of 15 cases. The marked success of CS and CS/IF docking shows that ensemble docking can be a versatile and effective method for accommodating conformational plasticity in docking and serves as a demonstration for the CS theory-that binding-competent conformers exist in the unbound ensemble and can be selected based on their favorable binding energies.
AB - Accommodating backbone flexibility continues to be the most difficult challenge in computational docking of protein-protein complexes. Towards that end, we simulate four distinct biophysical models of protein binding in RosettaDock, a multiscale Monte-Carlo-based algorithm that uses a quasi-kinetic search process to emulate the diffusional encounter of two proteins and to identify low-energy complexes. The four binding models are as follows: (1) key-lock (KL) model, using rigid-backbone docking; (2) conformer selection (CS) model, using a novel ensemble docking algorithm; (3) induced fit (IF) model, using energy-gradient-based backbone minimization; and (4) combined conformer selection/induced fit (CS/IF) model. Backbone flexibility was limited to the smaller partner of the complex, structural ensembles were generated using Rosetta refinement methods, and docking consisted of local perturbations around the complexed conformation using unbound component crystal structures for a set of 21 target complexes. The lowest-energy structure contained > 30% of the native residue-residue contacts for 9, 13, 13, and 14 targets for KL, CS, IF, and CS/IF docking, respectively. When applied to 15 targets using nuclear magnetic resonance ensembles of the smaller protein, the lowest-energy structure recovered at least 30% native residue contacts in 3, 8, 4, and 8 targets for KL, CS, IF, and CS/IF docking, respectively. CS/IF docking of the nuclear magnetic resonance ensemble performed equally well or better than KL docking with the unbound crystal structure in 10 of 15 cases. The marked success of CS and CS/IF docking shows that ensemble docking can be a versatile and effective method for accommodating conformational plasticity in docking and serves as a demonstration for the CS theory-that binding-competent conformers exist in the unbound ensemble and can be selected based on their favorable binding energies.
KW - NMR ensembles
KW - conformer selection
KW - ensemble docking
KW - flexible docking
KW - protein-protein docking
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U2 - 10.1016/j.jmb.2008.05.042
DO - 10.1016/j.jmb.2008.05.042
M3 - Article
C2 - 18640688
AN - SCOPUS:48449094112
SN - 0022-2836
VL - 381
SP - 1068
EP - 1087
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 4
ER -