Quantum Effects in Cation Interactions with Firstand Second Coordination Shell Ligands in Metalloproteins

摘要

Despite decades of investigations, the principal mechanisms responsible for the high affinity and specificity of proteins for key physiological cations K⁺, Na⁺, and Ca²⁺ 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 finitetemperature. Several solutions to this challenge have been proposedin the field, ranging from the recently developed Drude polarizableforce-field for simulations of metalloproteins to approximate tight-bindingdensity functional theory (DFTB). To delineate the usefulness of differentapproximations, we examined the accuracy of three recent and commonlyused theoretical models and numerical algorithms, namely, CHARMM C36,the latest developed Drude polarizable force fields, and DFTB3 withthe latest 3OB parameters. We performed MD simulations for 30 cation-selectiveproteins with high-resolution X-ray structures to create ensemblesof structures for analysis with different levels of theory, e.g.,additive and polarizable force fields, DFTB3, and DFT. The resultsfrom DFT computations were used to benchmark CHARMM C36, Drude, andDFTB3 performance. The explicit modeling of quantum effects unveilsthe key electrostatic properties of the protein sites and the importanceof specific ion-protein interactions. One of the most interestingfindings is that secondary coordination shells of proteins are noticeablyperturbed in a cation-dependent manner, showing significant delocalizationand long-range effects of charge transfer and polarization upon bindingCa²⁺.