title: Alchemical FEP Calculations of Ligand Conformer Focusing in Explicit Solvent.
abstract: Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of "focusing" on one specific conformational state that binds to a protein. The calculated conformer focusing term made a considerable difference of 5-10 kJ/mol in computed relative binding free energies of studied Syk inhibitors and significantly improved the resulting accuracy of predictions.
authors.affiliation: N. D. Zelinsky Institute Of Organic Chemistry (ZIOC RAS), Leninsky avenue, 47, 119991 Moscow, Russian Federation.|National Research Centre "Kurchatov Instititute" , Akademika Kurchatova pl., 1, 123182 Moscow, Russia.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Zeifman
authors.affiliation: N. D. Zelinsky Institute Of Organic Chemistry (ZIOC RAS), Leninsky avenue, 47, 119991 Moscow, Russian Federation.|Molecular Technologies, Ltd. , Leninskie gory, 1/75G, 119992, Moscow, Russian Federation.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Stroylov
authors.affiliation: N. D. Zelinsky Institute Of Organic Chemistry (ZIOC RAS), Leninsky avenue, 47, 119991 Moscow, Russian Federation.|Molecular Technologies, Ltd. , Leninskie gory, 1/75G, 119992, Moscow, Russian Federation.
authors.forename: Fedor N
authors.initials: FN
authors.lastname: Novikov
authors.affiliation: N. D. Zelinsky Institute Of Organic Chemistry (ZIOC RAS), Leninsky avenue, 47, 119991 Moscow, Russian Federation.|Molecular Technologies, Ltd. , Leninskie gory, 1/75G, 119992, Moscow, Russian Federation.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Stroganov
authors.affiliation: BioMolTech Corp. , 226 York Mills Road, Toronto, Ontario M2L 1L1, Canada.
authors.forename: Val
authors.initials: V
authors.lastname: Kulkov
authors.affiliation: N. D. Zelinsky Institute Of Organic Chemistry (ZIOC RAS), Leninsky avenue, 47, 119991 Moscow, Russian Federation.|Molecular Technologies, Ltd. , Leninskie gory, 1/75G, 119992, Moscow, Russian Federation.
authors.forename: Ghermes G
authors.initials: GG
authors.lastname: Chilov