Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

Ahmadi, Samad; Herrera, Lizandra Barrios; Chehelamirani, Morteza; Hostaš, Jiří; Jalife, Said; Salahub, Dennis R.

doi:10.1002/qua.25558

Cited by 153 publications

(165 citation statements)

References 272 publications

(336 reference statements)

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“…The various advantages, or difficulties, of different methods vary for the different possible systems that need to be calculated. The question has been considered in detail, and in generality, by Ahmadi et al [ 108 ].…”

Section: Computational Techniques: General Considerations Relatingmentioning

confidence: 99%

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Kariev

Green

2018

Sensors

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Over two-thirds of a century ago, Hodgkin and Huxley proposed the existence of voltage gated ion channels (VGICs) to carry Na+ and K+ ions across the cell membrane to create the nerve impulse, in response to depolarization of the membrane. The channels have multiple physiological roles, and play a central role in a wide variety of diseases when they malfunction. The first channel structure was found by MacKinnon and coworkers in 1998. Subsequently, the structure of a number of VGICs was determined in the open (ion conducting) state. This type of channel consists of four voltage sensing domains (VSDs), each formed from four transmembrane (TM) segments, plus a pore domain through which ions move. Understanding the gating mechanism (how the channel opens and closes) requires structures. One TM segment (S4) has an arginine in every third position, with one such segment per domain. It is usually assumed that these arginines are all ionized, and in the resting state are held toward the intracellular side of the membrane by voltage across the membrane. They are assumed to move outward (extracellular direction) when released by depolarization of this voltage, producing a capacitive gating current and opening the channel. We suggest alternate interpretations of the evidence that led to these models. Measured gating current is the total charge displacement of all atoms in the VSD; we propose that the prime, but not sole, contributor is proton motion, not displacement of the charges on the arginines of S4. It is known that the VSD can conduct protons. Quantum calculations on the Kv1.2 potassium channel VSD show how; the key is the amphoteric nature of the arginine side chain, which allows it to transfer a proton. This appears to be the first time the arginine side chain has had its amphoteric character considered. We have calculated one such proton transfer in detail: this proton starts from a tyrosine that can ionize, transferring to the NE of the third arginine on S4; that arginine’s NH then transfers a proton to a glutamate. The backbone remains static. A mutation predicted to affect the proton transfer has been qualitatively confirmed experimentally, from the change in the gating current-voltage curve. The total charge displacement in going from a normal closed potential of −70 mV across the membrane to 0 mV (open), is calculated to be approximately consistent with measured values, although the error limits on the calculation require caution in interpretation.

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Section: Computational Techniques: General Considerations Relatingmentioning

confidence: 99%

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Kariev

Green

2018

Sensors

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“…Cryo EM structures are of course also determined at low temperature. (An alternative, starting from snapshots of MD simulations (124), and then finding an energy minimum, seems to combine disadvantages of both methods.) By using a larger structure we minimize boundary issues.…”

Section: Results Of Recent Quantum Calculations On the Vsdmentioning

confidence: 99%

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Kariev

Green

2018

Preprint

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Over two-thirds of a century ago, Hodgkin and Huxley proposed the existence of voltage gated ion channels (VGIC) to carry Na + and K + ions across the cell membrane to create the nerve impulse, in response to depolarization of the membrane. The channels have multiple physiological roles, and play a central role in a wide variety of diseases when they malfunction. The first channel structure was found by MacKinnon and coworkers in 1998. Subsequently the structure of a number of VGIC was determined in the open (ion conducting) state. This type of channel consists of four voltage sensing domains (VSD), each formed from four transmembrane (TM) segments, plus a pore domain through which ions move.Understanding the gating mechanism (how the channel opens and closes) requires structures. One TM segment (S4) has an arginine in every third position, with one such segment per domain. It is usually assumed that these arginines are all ionized, and in the resting state are held toward the intracellular side of the membrane by voltage across the membrane. They are assumed to move outward (extracellular direction) when released by depolarization of this voltage, producing a capacitive gating current and opening the channel. We suggest alternate interpretations of the evidence that led to these models. Measured gating current is the total charge displacement of all atoms in the VSD; we propose that the prime, but not sole, contributor is proton motion, not displacement of the charges on the arginines of S4. It is known that the VSD can conduct protons. Quantum calculations on the K v 1.2 potassium channel VSD show how; the key is the amphoteric nature of the arginine side chain, which allows it to transfer a proton; this appears to be the first time the arginine side chain has had its amphoteric character considered. We have calculated one such proton transfer in detail: this proton starts from a tyrosine that can ionize, transferring to the NE of the third arginine on S4; that arginine's NH then transfers a proton to a glutamate. The backbone remains static. A mutation predicted to affect the proton transfer has been qualitatively confirmed experimentally, from the change in the gating current-voltage curve. The total charge displacement in going from a normal closed potential of -70 mV across the membrane to 0 mV (open), is calculated to be approximately consistent with measured values, although the error limits on the calculation require caution in interpretation.

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“…Enzyme substrates are generally small enough that they can be treated with modern quantum chemical methods, but enzymes themselves (and the solvent surrounding them), are too large. Thus, if one wishes to model a reaction, that is, bond making/breaking process(es), within an enzyme, methods that use quantum chemistry for part of the system and a force field for the rest are often used; these are the so‐called QM/MM (quantum mechanics/molecular mechanics) methods . Such combined methods can be very effective if applied appropriately; for example, the treatment of the border between the substructures treated with quantum chemistry and the rest of the system requires special attention.…”

Section: Methodsmentioning

confidence: 99%

“…Dynamics calculations provide more information, but are far more time consuming because trajectories are constructed from hundreds or thousands of static calculations. Fast events, that is, those occurring within hundreds of femtoseconds (fs) such as chemical bond making/breaking, for small models can be treated with ab initio molecular dynamics (AIMD), while slower events, for example, enzyme conformation changes, can be treated with classical molecular dynamics (MD) . Again, QM/MM implementations are possible .…”

Section: Methodsmentioning

confidence: 99%

Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

Tantillo

2019

WIREs Comput Mol Sci

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Quantum chemical methods are useful for probing the energetic viability of chemical mechanisms involved in natural product biosynthesis. Typical computational approaches are described and representative examples of mechanistic studies on radical, pericyclic, and carbocation rearrangement reactions that lead to polycyclic skeletons of complex natural products showcase the utility of such methods in providing understanding and shaping future experimental studies. The importance of inherent substrate reactivity is highlighted and cautions for interpreting computational results are discussed.

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Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

Cited by 153 publications

References 272 publications

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

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