Incorporation of side chain flexibility into protein binding pockets using MTflex.
The plasticity of active sites plays a significant role in drug recognition and binding, but the accurate incorporation of 'receptor flexibility' remains a significant computational challenge. Many approaches have been put forward to address receptor flexibility in docking studies by generating relevant ensembles on the energy surface. Herein, we describe the Movable Type with flexibility (MTflex) method that generates ensembles on the more relevant free energy surface in a computationally tractable manner. This novel approach enumerates conformational states based on side chain flexibility and then estimates their relative free energies using the MT methodology. The resultant conformational states can then be used in subsequent docking and scoring exercises. In particular, we demonstrate that using the MTflexensembles improves MT's ability to predict binding free energies over docking only to the crystal structure.
Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, MI 48824, United States.
Nupur
N
Bansal
Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, MI 48824, United States.
Zheng
Z
Zheng
Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, MI 48824, United States; Institute for Cyber Enabled Research, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, United States. Electronic address: kmerz1@gmail.com.
Kenneth M
KM
Merz
D062105:Molecular Docking Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013499:Surface Properties
D011506:Proteins
Binding free energy; Docking; Movable Type method; Receptor flexibility; Scoring