There is a vast gulf between the two primary strategies for simulating protein-ligand interactions. Docking methods significantly limit or eliminate protein flexibility to gain great speed at the price of uncontrolled inaccuracy, whereas fully flexible atomistic molecular dynamics simulations are expensive and often suffer from limited sampling. We are developing a flexible docking approach geared especially for highly flexible or poorly resolved targets based on mixed-resolution Monte Carlo (MRMC), which is intended to offer a balance among speed, protein flexibility, and sampling power. The binding region of the protein is treated with a standard atomistic force field, while the remainder of the protein is modeled at the residue level with a Go model that permits protein flexibility while saving computational cost. Implicit solvation is used. We have been testing the MRMC method with known ligands of estrogen receptor alpha, an important cancer target known for its flexibility. While MRMC docking takes substantially more CPU time for each individual ligand compared to standard docking, adding protein flexibility leads to significantly lower total energies, stronger interactions between protein and ligand, and for some ligands, docked conformations that are significantly closer to the crystal structure than those obtained for a rigid protein.

Systematic investigation of increased protein flexibility in protein-ligand docking with mixed-resolution Monte Carlo

253rd National Meeting (2017)

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