Protein-protein docking with a reduced protein model accounting for side-chain flexibility

Abstract

A protein-protein docking approach has been developed based on a reduced protein representation with up to three pseudo atoms per amino acid residue. Docking is performed by energy minimization in rotational and translational degrees of freedom. The reduced protein representation allows an efficient search for docking minima on the protein surfaces within. During docking, an effective energy function between pseudo atoms has been used based on amino acid size and physico-chemical character. Energy minimization of protein test complexes in the reduced representation results in geometries close to experiment with backbone root mean square deviations (RMSDs) of approximately 1 to 3 A for the mobile protein partner from the experimental geometry. For most test cases, the energy-minimized experimental structure scores among the top five energy minima in systematic docking studies when using both partners in their bound conformations. To account for side-chain conformational changes in case of using unbound protein conformations, a multicopy approach has been used to select the most favorable side-chain conformation during the docking process. The multicopy approach significantly improves the docking performance, using unbound (apo) binding partners without a significant increase in computer time. For most docking test systems using unbound partners, and without accounting for any information about the known binding geometry, a solution within approximately 2 to 3.5 A RMSD of the full mobile partner from the experimental geometry was found among the 40 top-scoring complexes. The approach could be extended to include protein loop flexibility, and might also be useful for docking of modeled protein structures.

Figure 1.

Comparison of the trypsin (light gray)-BPTI (dark gray) complex (PDB code 2PTC) at atomic resolution (A; each van der Waals sphere represents a heavy atom) and in the reduced model (B; each sphere represents a pseudo atom in the reduced protein model).

Figure 2.

Comparison of energy-minimized (Cα-backbone of mobile protein partner in bold) and experimental protein complexes (dashed line indicates ligand protein backbone; continuous line, receptor protein backbone). (A) Stereo view of the subtilisin/inhibitor complex (PDB entry 2SIC); (B) Stereo view of the α-chymotrypsin/ovomucoid complex (PDB entry 1CHO). Energy minimization has been performed in translational and rotational degrees of freedom of the ligand proteins by using the reduced protein model and starting from the corresponding experimental structures.

Figure 3.

(A) Number of distinct energy-minimized complexes (Nminima, within 10 energy units of the lowest-energy complex) versus the number of start configurations (Nstart) for systematic docking studies on the trypsin/BPTI (PDB entry 2PTC) system. Two energy minima are considered as distinct minima if the root mean square deviation of the mobile protein partner is >0.2 Å relative to other energy minima. (B) Number of docking trials that yielded the energy-minimized X-ray structure (Nxray) versus the number of docking start configurations spread over the surface of the receptor (Nstart).

Figure 4.

Comparison (stereo view) of energy minimization of the trypsin/BPTI complex using the bound (A; PDB code 2PTC), unbound (B; PDB codes 2PTN + 4PTI), and unbound conformations including side-chain copies on surface-exposed side-chains for BPTI (C), starting from the same placements as found in the experimental complex structure. The Cα-backbone of the mobile BPTI ligand protein after energy minimization is shown in bold (including the Lys₁₅ side chain at the docking interface). The backbone of BPTI in the experimental complex is shown as a dashed line (continuous thin line indicates backbone of trypsin in the experimental complex structure).