A high-performance QM/MM program

The Advantages of QM/MM methods

Insight into reactive chemistry is crucial to understanding the mechanism of drug receptor interactions in systems where the ligand is covalently bound to the receptor. For example, it's necessary to study the transition states between bound and unbound forms in order to design antibiotics that are not subject to inactivation by beta lactamases. Classical molecular mechanics (MM) methods cannot describe the electronic changes during a reaction, and are ill-equipped to address ligand-receptor interactions in systems containing metals.

Ab initio quantum mechanics (QM) is required to study reactive chemistry or interactions involving transition metals in a protein environment. However, even with today's computer technology, full QM calculations of entire proteins are still intractable.

Mixed QM/MM calculations provide the ideal solution by separating out the reactive core, which can be accurately described with QM, while treating the remainder of the complex more efficiently with MM. While QM/MM may not be needed for every structure-based drug design project, many important systems cannot be effectively addressed by any other computational means. QM/MM is therefore a key component in the arsenal of computational drug discovery.

High performance:
QSite outperforms other QM/MM programs because it takes advantage of Jaguar, long recognized as the industry leader in QM calculations.

Advanced technology:
QSite's innovative approach to the QM/MM interface specifically addresses protein systems and interactions between QM and MM regions. QSite also models crucial solvation effects.

Transition metal convergence:
QSite achieves a high degree of accuracy in metalloproteins thanks to Jaguar's advanced capabilities; it reliably and efficiently converges to the correct ground state of transition metal containing systems.

Wavefunction choices:
QSite offers different levels of theory to evaluate the QM region: Hartree Fock, DFT, and local MP2. This allows the user to choose the best balance between computational cost and accuracy.

Advanced calculation setup and analysis:
QSite automatically applies special interface parameters, making it simple to set up calculations. Computed results, such as molecular orbitals and electron densities, can be visualized within Maestro.

Citations and Acknowledgements

Schrödinger Release 2022-4: QSite, Schrödinger, LLC, New York, NY, 2021.

Murphy, R. B.; Philipp, D. M.; Friesner, R. A., "A mixed quantum mechanics/molecular mechanics (QM/MM) method for large-scale modeling of chemistry in protein environments," J. Comp. Chem., 2000, 21, 1442-1457

Philipp, D. M.; Friesner, R. A., "Mixed ab initio QM/MM modeling using frozen orbitals and tests with alanine dipeptide and tetrapeptide," J. Comp. Chem., 1999, 20, 1468-1494

"Light Harvesting by Equally Contributing Mechanisms in a Photosynthetic Antenna Protein"

Guberman-Pfeffer, M.J.; Greco, J.A.; Birge, R.R.; Frank, H.A.; Gascón, J.A., J. Phys. Chem. Lett., 2018, 9 (3), 563–568

· "Mechanistic and Computational Studies of the Reductive Half-Reaction of Tyrosine to Phenylalanine Active Site Variants of d-Arginine Dehydrogenase"

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"Water in the active site of ketosteroid isomerase"

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· "Insights into the different dioxygen activation pathways of methane and toluene monooxygenase hydroxylases"

Bochevarov, A.D.; Li, J.; Song, W.J.; Friesner, R.A.; Lippard, S.J., J. Am. Chem. Soc., 2011, 133, 7384-97

"Carbon Monoxide Dehydrogenase Reaction Mechanism: A Likely Case of Abnormal CO2 Insertion to a Ni-H- Bond"

Amara, P.; Mouesca, J. M.; Volbeda, A.; Fontecilla-Camps, J.C., Inorg. Chem., 2011, 50, 1868-1878

"Unexpected electron transfer mechanism upon AdoMet cleavage in radical SAM proteins"

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"Lead identification of acetylcholinesterase inhibitors–histamine H3 receptor antagonists from molecular modeling"

Bembenek, S.D.; Keith, J.M.; Letavic, M.A.; Apodaca, R.; Barbier, A.J.; Dvorak, L.; Aluisio, L.; Miller, K.L.; Lovenberg, T.W.; Carruthers, N.I., Bioorg. & Med. Chem., 2008, 16, 2968-2973

"Structure-guided discovery of cyclin-dependent kinase inhibitors"

Fischmann, T.O.; Hruza, A.; Duca, J.S.; Ramanathan, L.; Mayhood, T.; Windsor, W.T.; Le, H.V.; Guzi, T.J.; Dwyer, M.P.; Paruch, K.; Doll, R.J.; Lees, E.; Parry, D.; Seghezzi, W.; Madison, V., Biopolymers, 2008, 89, 372-379

"Intermediates in dioxygen activation by methane monooxygenase: a QM/MM study"

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"Modeling of Ligation-induced Helix/Loop Displacements in Myoglobin: Toward an Understanding of Hemoglobin Allostery"

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"Substrate Hydroxylation in Methane Monooxygenase: Quantitative Modeling via Mixed Quantum Mechanics/Molecular Mechanics Techniques"

Gherman, B. F.; Lippard, S. J.; Friesner R. A., J. Am. Chem. Soc., 2005, 127, 1025-1037

"Mixed Quantum Mechanical/ Molecular Mechanical (QM/MM) Study of the Deacylation Reaction in a Penicillin Binding Protein (PBP) Versus in a Class C β-Lactamase "

Gherman, B.F.; Goldberg, S. D.; Cornish, V. W.; Friesner, R. A., J. Am. Chem. Soc. , 2004, 126, 7652-7664

"Cytochrome P450CAM Enzymatic Catalysis Cycle: A Quantum Mechanics/Molecular Mechanics Study"

Guallar, V.; Friesner, R. A., J. Am. Chem. Soc. , 2004, 126, 8501-8508

"Dioxygen Activation in Methane Monooxygenase: A Theoretical Study"

Gherman, B. F.; Baik, M.; Lippard, S. J.; Friesner, R. A., J. Am. Chem. Soc., 2004, 126, 2978-2990

"Theoretical Study of Cisplatin Binding to Purine Bases: Why Does Cisplatin Prefer Guanine over Adenine as Substrate?"

Baik, M.; Friesner, R. A.; Lippard, S. J., J. Am. Chem. Soc., 2003, 125, 14082-14092

"Reversible Dioxygen Binding to Hemerythrin"

Wirstam, M; Lippard, S.J.; Friesner, R.A., J. Am. Chem. Soc. , 2003, 125, 3980-3987

"Peripheral Heme Substituents Control the Hydrogen-Atom Abstraction Chemistry in Cytochromes P450"

Guallar, V.; Baik, M.; Lippard, S. J.; Friesner, R. A., Proc. Nat. Acad. Sci. USA, 2003, 100, 6998-7002

"How Iron-containing Proteins Control Dioxygen Chemistry: A Detailed Atomic Level Description via Accurate Quantum Chemical and Mixed Quantum Mechanics/Molecular Mechanics Calculations"

Friesner, R. A.; Baik, M.; Guallar, V.; Gherman, B. F.; Wirstam, M.; Murphy, R. B.; Lippard, S. J., Coordination Chemistry Reviews, 2003, , 238-239, 267-290

"Mechanistic Studies on the Hydroxylation of Methane by Methane Monooxygenase"

Baik, M.; Newcomb, M.; Friesner, R. A.; Lippard, S. J., Chemical Reviews, 2003, 103, 2385-2419

"Hydroxylation of Methane by Non-Heme Diiron Enzymes: Molecular Orbital Analysis of the C-H Bond Activation by Reactive Intermediate Q"

Baik, M.; Gherman, B. F.; Friesner, R. A., Lippard, S. J., J. Am. Chem. Soc., 2002, 124, 14608-14615

"A Mixed Quantum Mechanics/Molecular Mechanics (QM/MM) Method for Large-scale Modeling of Chemistry in Protein Environments"

Murphy, R. B.; Philipp, D. M.; Friesner, R. A., J. Comp. Chem., 2000, 21, 1442-1457

"Mixed ab initio QM/MM Modeling Using Frozen Orbitals and Tests with Alanine Dipeptide and Tetrapeptide"

Philipp, D. M.; Friesner, R. A., J. Comp. Chem., 1999, 20, 1468-1494
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