title: Energy Decomposition Analysis Based on Absolutely Localized Molecular Orbitals for Large-Scale Density Functional Theory Calculations in Drug Design.
abstract: We report the development and implementation of an energy decomposition analysis (EDA) scheme in the ONETEP linear-scaling electronic structure package. Our approach is hybrid as it combines the localized molecular orbital EDA (Su, P.; Li, H. J. Chem. Phys., 2009, 131, 014102) and the absolutely localized molecular orbital EDA (Khaliullin, R. Z.; et al. J. Phys. Chem. A, 2007, 111, 8753-8765) to partition the intermolecular interaction energy into chemically distinct components (electrostatic, exchange, correlation, Pauli repulsion, polarization, and charge transfer). Limitations shared in EDA approaches such as the issue of basis set dependence in polarization and charge transfer are discussed, and a remedy to this problem is proposed that exploits the strictly localized property of the ONETEP orbitals. Our method is validated on a range of complexes with interactions relevant to drug design. We demonstrate the capabilities for large-scale calculations with our approach on complexes of thrombin with an inhibitor comprised of up to 4975 atoms. Given the capability of ONETEP for large-scale calculations, such as on entire proteins, we expect that our EDA scheme can be applied in a large range of biomolecular problems, especially in the context of drug design.
authors.affiliation: School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: M J S
authors.initials: MJ
authors.lastname: Phipps
authors.affiliation: Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG , 88397 Biberach, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Fox
authors.affiliation: Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG , 88397 Biberach, Germany.
authors.forename: C S
authors.initials: CS
authors.lastname: Tautermann
authors.affiliation: School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: C-K
authors.initials: CK
authors.lastname: Skylaris
mesh_terms: D015195:Drug Design; D004734:Energy Metabolism; D006860:Hydrogen Bonding; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D011506:Proteins