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

  • Ewa I. Chudyk
  • Laurie Sarrat
  • Matteo Aldeghi
  • Dmitri G. Fedorov
  • Mike J. Bodkin
  • Tim James
  • Michelle Southey
  • Roger Robinson
  • Inaki Morao
  • Alexander HeifetzEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)


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.

Key words

GPCR G-protein-coupled receptors Chemical interactions Pair-interaction energy Drugs Receptor Modeling QM Quantum Mechanics FMO Fragment Molecular Orbitals method CADD Computer-Aided Drug Design SBDD Structure Based Drug Design GAMESS General Atomic and Molecular Electronic Structure System PIEDA Pair Interaction Energies Decomposition Analysis 



A.H. and R.R. would like to acknowledge the support of EU H2020 CompBioMed project ( and the BBSRC Flexible Interchanger Programme project (BB/P004245/1).


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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Ewa I. Chudyk
    • 1
  • Laurie Sarrat
    • 1
  • Matteo Aldeghi
    • 1
  • Dmitri G. Fedorov
    • 2
  • Mike J. Bodkin
    • 1
  • Tim James
    • 1
  • Michelle Southey
    • 1
  • Roger Robinson
    • 1
  • Inaki Morao
    • 1
  • Alexander Heifetz
    • 1
    Email author
  1. 1.Evotec (UK) Ltd.AbingdonUK
  2. 2.CD-FMat, National Institute of Advanced Industrial Science and Technology (AIST)TsukubaJapan

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