The appropriate selection of initial receptor structure has been the "cornerstone" or
foundation of successful structure-based virtual screening (SBVS), and plagued the structure-based
design with a significant practical problem to determine the major physiological states or important
transition states of receptors (e.g. proteins with multiple low-energy conformations and liganddependent
conformational dynamics). It is well known that current SBVS methods lack the
capacity to capture and characterize the intrinsic receptor flexibility with ideal cost-effectiveness.
In recent years, cryoelectron microscopy (cryo-EM) has been routinely applied in the
determination of biomolecular assemblies within the physiological state. In this work, we review
the roles of cryo-EM and ensemble docking methods to present the intrinsically dynamic behavior
of biomacromolecules, as well as the ever-improving estimation of ligand binding affinities and
receptor-ligand thermodynamics. Finally, we also provide a viewpoint for further research works
on modeling receptor dynamics.
Keywords: Molecular recognition, receptor dynamics, Cryo-EM, flexible docking, molecular simulation.
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