title: Quantum effects in cation interactions with first and second coordination shell ligands in metalloproteins.
abstract: Despite decades of investigations, the principal mechanisms responsible for the high affinity and specificity of proteins for key physiological cations K(+), Na(+), and Ca(2+) remain a hotly debated topic. At the core of the debate is an apparent need (or lack thereof) for an accurate description of the electrostatic response of the charge distribution in a protein to the binding of an ion. These effects range from partial electronic polarization of the directly ligating atoms to long-range effects related to partial charge transfer and electronic delocalization effects. While accurate modeling of cation recognition by metalloproteins warrants the use of quantum-mechanics (QM) calculations, the most popular approximations used in major biomolecular simulation packages rely on the implicit modeling of electronic polarization effects. That is, high-level QM computations for ion binding to proteins are desirable, but they are often unfeasible, because of the large size of the reactive-site models and the need to sample conformational space exhaustively at finite temperature. Several solutions to this challenge have been proposed in the field, ranging from the recently developed Drude polarizable force-field for simulations of metalloproteins to approximate tight-binding density functional theory (DFTB). To delineate the usefulness of different approximations, we examined the accuracy of three recent and commonly used theoretical models and numerical algorithms, namely, CHARMM C36, the latest developed Drude polarizable force fields, and DFTB3 with the latest 3OB parameters. We performed MD simulations for 30 cation-selective proteins with high-resolution X-ray structures to create ensembles of structures for analysis with different levels of theory, e.g., additive and polarizable force fields, DFTB3, and DFT. The results from DFT computations were used to benchmark CHARMM C36, Drude, and DFTB3 performance. The explicit modeling of quantum effects unveils the key electrostatic properties of the protein sites and the importance of specific ion-protein interactions. One of the most interesting findings is that secondary coordination shells of proteins are noticeably perturbed in a cation-dependent manner, showing significant delocalization and long-range effects of charge transfer and polarization upon binding Ca(2+).
authors.affiliation: Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary , Calgary, Alberta, Canada T2N 1N4.
authors.forename: Van
authors.initials: V
authors.lastname: Ngo
authors.affiliation: Centre for Molecular Simulation, Institute for Quantum Science and Technology and Department of Chemistry, University of Calgary , Calgary, Alberta, Canada T2N 1N4.
authors.forename: Mauricio C
authors.initials: MC
authors.lastname: da Silva
authors.affiliation: Institute of Physical Chemistry, Karlsruhe Institute of Technology , Kaiserstr. 12, 76021 Karlsruhe, Germany.|Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kubillus
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.affiliation: Institute of Physical Chemistry, Karlsruhe Institute of Technology , Kaiserstr. 12, 76021 Karlsruhe, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Elstner
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Centre for Molecular Simulation, Institute for Quantum Science and Technology and Department of Chemistry, University of Calgary , Calgary, Alberta, Canada T2N 1N4.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Salahub
authors.affiliation: Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary , Calgary, Alberta, Canada T2N 1N4.
authors.forename: Sergei Yu
authors.initials: SY
authors.lastname: Noskov
mesh_terms: D002118:Calcium / Q000737:chemistry*; D002412:Cations / Q000737:chemistry; D008024:Ligands; D008667:Metalloproteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000737:chemistry*; D011789:Quantum Theory; D012964:Sodium / Q000737:chemistry*
chemical_list: D002412:Cations; D008024:Ligands; D008667:Metalloproteins; D012964:Sodium; D011188:Potassium; D002118:Calcium