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.

There has been fantastic progress in solving GPCR crystal structures. However, the ability of X-ray crystallography to guide the drug discovery process for GPCR targets is limited by the availability of accurate tools to explore receptorligand interactions. Visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum Mechanics approaches (QM) are often too computationally expensive, but the Fragment Molecular Orbital (FMO) method offers an excellent solution that combines accuracy, speed and the ability to reveal key interactions that would otherwise be hard to detect. Integration of GPCR crystallography or homology modelling with FMO reveals atomistic details of the individual contributions of each residue and water molecule towards ligand binding, including an analysis of their chemical nature.

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