Conference: 75th Annual Meeting of the American Crystallographic Association

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Session: 2.2.1 Emerging Modalities in Pharma Part 2 – July 20: 3:46 PM (CDT)

Title: Improving macromolecular models of challenging ligands through combined QM/MM X-ray refinement

Authors: Margarita A Tararina¹, Lance M Westerhoff², Oleg Borbulevych², Matt Pokross¹, David A Critton^1
1 Bristol Myers Squibb, Princeton, NJ, USA. ² QuantumBio, Inc., State College, PA, USA

Abstract:

Conventional structural refinement relies on fixed stereochemical restraints for all components within the protein-ligand complex, using pre-determined parameters such as bond lengths, angles, and torsions in the unbound ligand conformation. This approach can be challenging for non-standard modalities like covalent modifiers and macrocycles, where conformational flexibility is inherent to their mechanism of action, and the bound vs. unbound states differ significantly. To address this limitation and achieve a more complete model, we employ an automated molecular refinement approach that replaces stereochemical restraint gradients with quantum-mechanic/molecular mechanic (QM/MM) gradients in standard refinement packages, Phenix and Buster. In this context, we present user test cases in QM/MM structure refinement using QuantumBio’s DivCon plugin with XModeScore to explore potential ligand states and evaluate binding modes based on ligand strain energy and the z-score of difference density.

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Session: 3.1.5 Flexibility, Dynamics & The Secret Lives of Proteins – July 21: 10:50 AM (CDT)

Title: Atomic Detail from Disordered Regions: QM/MM-Based Real-Space Reconstruction of Loops, Rotamers, and Protonation States in X-ray/Cryo-EM Density

Authors: Lance M Westerhoff PhD¹ and Oleg Borbulevych^1
1 QuantumBio, Inc., State College, PA, USA

Abstract:

Protein flexibility is central to function—governing allosteric regulation, catalysis, signal transduction, and drug binding. Yet, this flexibility is often underrepresented in structural models derived from X-ray or Cryo-EM experiments, where flexible loops, alternate protonation states, and mobile side chains are frequently unresolved or omitted. These omissions limit the accuracy of molecular dynamics (MD), free energy calculations, and mechanistic insights. In this talk, we present a density-driven, quantum-informed protocol for reconstructing disordered and flexible regions of macromolecular structures, enabling more complete and chemically accurate models suitable for dynamic simulation and predictive design… more