Using explicit-water molecular dynamics simulations of a generic pocket-ligand model, we investigate how chemical and shape anisotropy of small ligands influences the affinities, kinetic rates, and pathways for their association with hydrophobic binding sites. In particular, we investigate aromatic compounds, all of similar molecular size, but distinct by various hydrophilic or hydrophobic residues. We demonstrate that the most hydrophobic sections are in general desolvated primarily upon binding to the cavity, suggesting that specific hydration of the different chemical units can steer the orientation pathways via a “hydrophobic torque.” Moreover, we find that ligands with bimodal orientation fluctuations have significantly increased kinetic barriers for binding compared to the kinetic barriers previously observed for spherical ligands due to translational fluctuations. We exemplify that these kinetic barriers, which are ligand specific, impact both binding and unbinding times for which we observe considerable differences between our studied ligands.
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7 September 2018
Research Article|
September 06 2018
Affinity, kinetics, and pathways of anisotropic ligands binding to hydrophobic model pockets
R. Gregor Weiß
;
R. Gregor Weiß
a)
1
Institut für Physik, Humboldt-Universität zu Berlin
, Newtonstraße 15, D-12489 Berlin, Germany
2
Laboratory of Physical Chemistry
, ETH Zürich, CH-8093 Zürich, Switzerland
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Richard Chudoba;
Richard Chudoba
1
Institut für Physik, Humboldt-Universität zu Berlin
, Newtonstraße 15, D-12489 Berlin, Germany
3
Research Group Simulations of Energy Materials, Helmholtz-Zentrum Berlin
, Hahn-Meitner-Platz 1, D-14109 Berlin, Germany
4
Physikalisches Institut, Albert-Ludwigs-Universität Freiburg
, Hermann-Herder Straße 3, D-79104 Freiburg, Germany
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Piotr Setny
;
Piotr Setny
5
Centre of New Technologies, University of Warsaw
, Stefana Banacha 2c, 00-927 Warsaw, Poland
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Joachim Dzubiella
Joachim Dzubiella
b)
1
Institut für Physik, Humboldt-Universität zu Berlin
, Newtonstraße 15, D-12489 Berlin, Germany
3
Research Group Simulations of Energy Materials, Helmholtz-Zentrum Berlin
, Hahn-Meitner-Platz 1, D-14109 Berlin, Germany
4
Physikalisches Institut, Albert-Ludwigs-Universität Freiburg
, Hermann-Herder Straße 3, D-79104 Freiburg, Germany
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J. Chem. Phys. 149, 094902 (2018)
Article history
Received:
February 07 2018
Accepted:
August 20 2018
Citation
R. Gregor Weiß, Richard Chudoba, Piotr Setny, Joachim Dzubiella; Affinity, kinetics, and pathways of anisotropic ligands binding to hydrophobic model pockets. J. Chem. Phys. 7 September 2018; 149 (9): 094902. https://doi.org/10.1063/1.5025118
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