QuantumBio will be presenting at the 2025 American Chemical Society Fall Meeting in Washington, DC.

 

PAPER TITLE: Advanced methods of protein structure preparation using X-ray/cryo-EM Data data with focus on loop flexibility: Implications for MD simulations and drug design

ORGANIZING DIVISIONS/COMMITTEES: COMP: Division of Computers in Chemistry
SESSION: Drug Design
SESSION TIME: 2:00 PM – 5:45 PM

PRESENTATION FORMAT: Oral – In-person
DAY & TIME OF PRESENTATION: Monday, August 18, 2025 from 5:30 PM – 5:45 PM
ROOM & LOCATION: Room 154B – Walter E. Washington Convention Center

Abstract:

Flexible protein loops play a crucial role in molecular dynamics (MD) simulations of protein-ligand interactions, as they contribute to the realistic modeling of protein conformational changes, ligand binding, and overall system stability. Many ligands bind to active sites or pockets surrounded by flexible loops, which can adapt to ligand binding by opening and closing. For example, the hinge movement of kinase loops allows for ATP binding and inhibitor specificity. However, such loops are typically poorly resolved or disordered in X-ray crystallography and Cryo-EM experiments, and their coordinates are often not included in the final structures.

Thus, flexible loops are essential for accurate and realistic MD simulations of protein-ligand interactions, as well as Free Energy Perturbation (FEP) calculations. As part of QuantumBio’s DivCon Discovery Suite, we developed an advanced, density-driven protocol to reconstruct missing regions of protein structures, including both backbone and side-chain atoms. This is followed by real-space (RS) refinement, in which geometry energy and gradients—derived using a QM, MM, or mixed QM/MM Hamiltonian—are combined with electron density values and gradients obtained from X-ray data or Cryo-EM maps [1-3]. The selection of optimal loop conformations is guided by the Z-score of the difference density (ZDD), based on experimental data.

In this study, we carefully select a diverse set of PDB structures with missing flexible loops of varying sizes in the vicinity of bound ligands. All missing structural components are generated using the QuantumBio protocol, followed by 100-nanosecond MD simulations. The impact of missing flexible loops on structural stability, as well as the correlation between ligand and loop movements in MD simulations, is analyzed in detail.

[1] Borbulevych, O. Y., Plumley, J. A., Martin, R. I., Merz K. M. & Westerhoff, L. M. (2014). Acta Cryst., D70, 1233.

[2] Borbulevych, O. Y., Martin, R. I. & Westerhoff, L. M. (2018). Acta Cryst., D74, 1063.

[3] Borbulevych, O. Y., Martin, R. I. & Westerhoff, L. M. (2021). J. Comput. Aided Mol. Des., 35, 433.