Exploring GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method

• Published in: Methods in molecular biology (Clifton, N.J.) Vol. 1705; p. 179
• Main Authors: Chudyk, Ewa I, Sarrat, Laurie, Aldeghi, Matteo, Fedorov, Dmitri G, Bodkin, Mike J, James, Tim, Southey, Michelle, Robinson, Roger, Morao, Inaki, Heifetz, Alexander
• Format: Journal Article
• Language: English
• Published: United States 01.01.2018
• Subjects: Algorithms; Drug Design; Drug Discovery - methods; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Quantitative Structure-Activity Relationship; Receptors, G-Protein-Coupled - metabolism; Drugs; PIEDA; CADD; General Atomic and Molecular Electronic Structure System; Quantum Mechanics; Fragment Molecular Orbitals method; FMO; SBDD; Modeling; Pair Interaction Energies Decomposition Analysis; GPCR G-protein-coupled receptors; GAMESS; Computer-Aided Drug Design; Receptor; Chemical interactions; Structure Based Drug Design; Pair-interaction energy; QM
• ISSN: 1940-6029
• DOI: 10.1007/978-1-4939-7465-8_8

The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity. It is essential for an efficient structure-based drug design (SBDD) process. FMO enables ab initio approaches to be applied to systems that conventional quantum-mechanical (QM) methods would find challenging. The key advantage of the Fragment Molecular Orbital Method (FMO) is that it can reveal atomistic details about the individual contributions and chemical nature of each residue and water molecule toward ligand binding which would otherwise be difficult to detect without using QM methods. In this chapter, we demonstrate the typical use of FMO to analyze 19 crystal structures of β1 and β2 adrenergic receptors with their corresponding agonists and antagonists.