Modeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable Potential

As the second most abundant cation in the human body, zinc is vital for the structures and functions of many proteins. Zinc-containing matrix metalloproteinases (MMPs) have been widely investigated as potential drug targets in a range of diseases ranging from cardiovascular disorders to cancers. However, it remains a challenge in theoretical studies to treat zinc in proteins with classical mechanics. In this study, we examined Zn²⁺ coordination with organic compounds and protein side chains using a polarizable atomic multipole-based electrostatic model. We find that the polarization effect plays a determining role in Zn²⁺ coordination geometry in both matrix metalloproteinase (MMP) complexes and zinc-finger proteins. In addition, the relative binding free energies of selected inhibitors binding with MMP13 have been estimated and compared with experimental results. While not directly interacting with the small molecule inhibitors, the permanent and polarizing field of Zn²⁺ exerts a strong influence on the relative affinities of the ligands. The simulation results also reveal that the polarization effect on binding is ligand-dependent and thus difficult to incorporate into fixed-charge models implicitly

Toward a Deeper Understanding of Enzyme Reactions Using the Coupled ELF/NCI Analysis: Application to DNA Repair Enzymes

The combined Electron Localization Funtion (ELF)/ Noncovalent Interaction (NCI) topological analysis (Gillet et al. <i>J. Chem. Theory Comput.</i> <b>2012</b>, <i>8</i>, 3993) has been extended to enzymatic reaction paths. We applied ELF/NCI to the reactions of DNA polymerase λ and the ε subunit of DNA polymerase III. ELF/NCI is shown to provide insights on the interactions during the evolution of enzymatic reactions including predicting the location of TS from structures located earlier along the reaction coordinate, differential metal coordination, and on barrier differences with two different cations

Toward a Deeper Understanding of Enzyme Reactions Using the Coupled ELF/NCI Analysis: Application to DNA Repair Enzymes

The combined Electron Localization Funtion (ELF)/ Noncovalent Interaction (NCI) topological analysis (Gillet et al. <i>J. Chem. Theory Comput.</i> <b>2012</b>, <i>8</i>, 3993) has been extended to enzymatic reaction paths. We applied ELF/NCI to the reactions of DNA polymerase λ and the ε subunit of DNA polymerase III. ELF/NCI is shown to provide insights on the interactions during the evolution of enzymatic reactions including predicting the location of TS from structures located earlier along the reaction coordinate, differential metal coordination, and on barrier differences with two different cations

QM/MM Simulations with the Gaussian Electrostatic Model: A Density-based Polarizable Potential

The use of advanced polarizable potentials in quantum mechanical/molecular mechanical (QM/MM) simulations has been shown to improve the overall accuracy of the calculation. We have developed a density-based potential called the Gaussian electrostatic model (GEM), which has been shown to provide very accurate environments for QM wave functions in QM/MM. In this contribution we present a new implementation of QM/GEM that extends our implementation to include all components (Coulomb, exchange–repulsion, polarization, and dispersion) for the total intermolecular interaction energy in QM/MM calculations, except for the charge-transfer term. The accuracy of the method is tested using a subset of water dimers from the water dimer potential energy surface reported by Babin et al. (<i>J. Chem. Theory Comput.</i> <b>2013</b> <i>9</i>, 5395–5403). Additionally, results of the new implementation are contrasted with results obtained with the classical AMOEBA potential. Our results indicate that GEM provides an accurate MM environment with average root-mean-square error <0.15 kcal/mol for every intermolecular interaction energy component compared with SAPT2+3/aug-cc-pVTZ reference calculations

QM/MM Simulations with the Gaussian Electrostatic Model: A Density-based Polarizable Potential

The use of advanced polarizable potentials in quantum mechanical/molecular mechanical (QM/MM) simulations has been shown to improve the overall accuracy of the calculation. We have developed a density-based potential called the Gaussian electrostatic model (GEM), which has been shown to provide very accurate environments for QM wave functions in QM/MM. In this contribution we present a new implementation of QM/GEM that extends our implementation to include all components (Coulomb, exchange–repulsion, polarization, and dispersion) for the total intermolecular interaction energy in QM/MM calculations, except for the charge-transfer term. The accuracy of the method is tested using a subset of water dimers from the water dimer potential energy surface reported by Babin et al. (<i>J. Chem. Theory Comput.</i> <b>2013</b> <i>9</i>, 5395–5403). Additionally, results of the new implementation are contrasted with results obtained with the classical AMOEBA potential. Our results indicate that GEM provides an accurate MM environment with average root-mean-square error <0.15 kcal/mol for every intermolecular interaction energy component compared with SAPT2+3/aug-cc-pVTZ reference calculations

Coupling Quantum Interpretative Techniques: Another Look at Chemical Mechanisms in Organic Reactions

A cross ELF/NCI analysis is tested over prototypical organic reactions. The synergetic use of ELF and NCI enables the understanding of reaction mechanisms since each method can respectively identify <b>regions of strong and weak electron pairing</b>. Chemically intuitive results are recovered and enriched by the identification of new features. Noncovalent interactions are found to foresee the evolution of the reaction from the initial steps. Within NCI, no topological catastrophe is observed as changes are continuous to such an extent that future reaction steps can be predicted from the evolution of the initial NCI critical points. Indeed, strong convergences through the reaction paths between ELF and NCI critical points enable identification of key interactions at the origin of the bond formation. VMD scripts enabling the automatic generation of movies depicting the cross NCI/ELF analysis along a reaction path (or following a Born–Oppenheimer molecular dynamics trajectory) are provided as Supporting Information

Elucidating the Phosphate Binding Mode of Phosphate-Binding Protein: The Critical Effect of Buffer Solution

Phosphate is an essential component of cell functions, and the specific transport of phosphorus into a cell is mediated by phosphate-binding protein (PBP). The mechanism of PBP-phosphate recognition remains controversial: on the basis of similar binding affinities at acidic and basic pHs, it is believed that the hydrogen network in the binding site is flexible to adapt to different protonation states of phosphates. However, only hydrogen (1H) phosphate was observed in the sub-angstrom X-ray structures. To address this inconsistency, we performed molecular dynamics simulations using the AMOEBA polarizable force field. Structural and free energy data from simulations suggested that 1H phosphate was the preferred bound form at both pHs. The binding of dihydrogen (2H) phosphate disrupted the hydrogen-bond network in the PBP pocket, and the computed affinity was much weaker than that of 1H phosphate. Furthermore, we showed that the discrepancy in the studies described above is resolved if the interaction between phosphate and the buffer agent is taken into account. The calculated apparent binding affinities are in excellent agreement with experimental measurements. Our results suggest the high specificity of PBP for 1H phosphate and highlight the importance of the buffer solution for the binding of highly charged ligands

Coupling Quantum Interpretative Techniques: Another Look at Chemical Mechanisms in Organic Reactions

A cross ELF/NCI analysis is tested over prototypical organic reactions. The synergetic use of ELF and NCI enables the understanding of reaction mechanisms since each method can respectively identify <b>regions of strong and weak electron pairing</b>. Chemically intuitive results are recovered and enriched by the identification of new features. Noncovalent interactions are found to foresee the evolution of the reaction from the initial steps. Within NCI, no topological catastrophe is observed as changes are continuous to such an extent that future reaction steps can be predicted from the evolution of the initial NCI critical points. Indeed, strong convergences through the reaction paths between ELF and NCI critical points enable identification of key interactions at the origin of the bond formation. VMD scripts enabling the automatic generation of movies depicting the cross NCI/ELF analysis along a reaction path (or following a Born–Oppenheimer molecular dynamics trajectory) are provided as Supporting Information

Coupling Quantum Interpretative Techniques: Another Look at Chemical Mechanisms in Organic Reactions

A cross ELF/NCI analysis is tested over prototypical organic reactions. The synergetic use of ELF and NCI enables the understanding of reaction mechanisms since each method can respectively identify <b>regions of strong and weak electron pairing</b>. Chemically intuitive results are recovered and enriched by the identification of new features. Noncovalent interactions are found to foresee the evolution of the reaction from the initial steps. Within NCI, no topological catastrophe is observed as changes are continuous to such an extent that future reaction steps can be predicted from the evolution of the initial NCI critical points. Indeed, strong convergences through the reaction paths between ELF and NCI critical points enable identification of key interactions at the origin of the bond formation. VMD scripts enabling the automatic generation of movies depicting the cross NCI/ELF analysis along a reaction path (or following a Born–Oppenheimer molecular dynamics trajectory) are provided as Supporting Information

Coupling Quantum Interpretative Techniques: Another Look at Chemical Mechanisms in Organic Reactions

A cross ELF/NCI analysis is tested over prototypical organic reactions. The synergetic use of ELF and NCI enables the understanding of reaction mechanisms since each method can respectively identify <b>regions of strong and weak electron pairing</b>. Chemically intuitive results are recovered and enriched by the identification of new features. Noncovalent interactions are found to foresee the evolution of the reaction from the initial steps. Within NCI, no topological catastrophe is observed as changes are continuous to such an extent that future reaction steps can be predicted from the evolution of the initial NCI critical points. Indeed, strong convergences through the reaction paths between ELF and NCI critical points enable identification of key interactions at the origin of the bond formation. VMD scripts enabling the automatic generation of movies depicting the cross NCI/ELF analysis along a reaction path (or following a Born–Oppenheimer molecular dynamics trajectory) are provided as Supporting Information