Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations

Ono, Junichi; KOSHIMIZU, Uika; Fukunishi, Yoshifumi; Nakai, Hiromi

doi:10.1016/j.cplett.2022.139489

Cited by 6 publications

(9 citation statements)

References 52 publications

(60 reference statements)

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“…This limitation causes the system to become trapped in one of the abundant local minima and makes it impractical to access reliable physical quantities, including the free-energy landscape. The improved sampling of rare events under investigation can be addressed by combining it with the so-called enhanced sampling methods. − Among several popular enhanced sampling methods, some of our calculations ,,,− have relied on the metadynamics (MTD) technique. − The MTD method biases the dynamics by frequently depositing repulsive potentials in the space of predefined collective variables (CVs). The accumulated bias potentials become a negative value of the free-energy surface (FES) along the CV if the simulation is sufficiently long.…”

Section: Theorymentioning

confidence: 99%

“…The performance of MTD can be improved with advanced algorithms such as well-tempered (WT) and multiple walkers (MW) variants in terms of the smooth convergence of FES and sampling efficiency, respectively. Our latest applications demonstrated that DC-based QM-MD/MTD simulations could treat chemical reactions in condensed-phase systems containing more than 10 4 atoms. − …”

Section: Theorymentioning

confidence: 99%

“…In 2005, a cubic water box containing 216 molecules was simulated using DC-based and HF-type SE methods . The DFTB method was applied along with the DC method in the 2000s to analyze the structure, mechanics, and dynamics of protein, amylose chain, and bulk water systems. − In the last several years, more than 30 computational studies have been reported by utilizing the DCDFTBMD (or its predecessor) program introduced in section . ,− ,,,− ,,− ,,,,− …”

Section: Illustrative Applicationsmentioning

confidence: 99%

“…Treating large biological macromolecules has been a route to illustrate potential applicability of the DC-based approximate electronic structure methods in several pioneering studies. ,,− DC-based DFTB-MD/MTD simulations have been successfully exploited for biomolecular systems, ranging from an alanine dipeptide toy model to photoreceptor proteins with realistic surrounding environments. ,,− QM/MM simulations have become popular for biological applications, , yet the present full QM treatment no longer suffers from proper determination of the boundary between QM and MM regions. The first, second, and third proton transfer mechanisms in bacteriorhodopsin were examined using recently observed intermediate structural snapshots by experiment. ,, The system size of approximately 50,000 for the latter two simulations is worth remarking as QM-MD, while even larger simulation models containing ∼80,000 atoms were treated in the latest study on the main protease in severe acute respiratory syndrome coronavirus 2 . Besides such chemical reactions in the ground-state, the developed DC-based TDDFTB method was applied to excited-state dynamics for biochemically important molecules. , …”

Section: Illustrative Applicationsmentioning

confidence: 99%

“…276,278,280 The system size of approximately 50,000 for the latter two simulations is worth remarking as QM-MD, while even larger simulation models containing ∼80,000 atoms were treated in the latest study on the main protease in severe acute respiratory syndrome coronavirus 2. 279 Besides such chemical reactions in the ground-state, the developed DC-based TDDFTB method was applied to excited-state dynamics for biochemically important molecules. 137,138 Applications of DC-based calculations to solids and surfaces have attracted interest in the early development phase of the DC method.…”

Section: Applications Of Divide-and-conquer Molecularmentioning

confidence: 99%

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Divide-and-Conquer Linear-Scaling Quantum Chemical Computations

et al. 2023

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Fragmentation and embedding schemes are of great importance when applying quantum-chemical calculations to more complex and attractive targets. The divide-and-conquer (DC)-based quantum-chemical model is a fragmentation scheme that can be connected to embedding schemes. This feature article explains several DC-based schemes developed by the authors over the last two decades, which was inspired by the pioneering study of DC self-consistent field (SCF) method by Yang and Lee (J. Chem. Phys. 1995, 103, 5674−5678). First, the theoretical aspects of the DC-based SCF, electron correlation, excited-state, and nuclear orbital methods are described, followed by the two-component relativistic theory, quantummechanical molecular dynamics simulation, and the introduction of three programs, including DC-based schemes. Illustrative applications confirmed the accuracy and feasibility of the DC-based schemes.

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Section: Theorymentioning

confidence: 99%

Section: Theorymentioning

confidence: 99%

Section: Illustrative Applicationsmentioning

confidence: 99%

Section: Illustrative Applicationsmentioning

confidence: 99%

Section: Applications Of Divide-and-conquer Molecularmentioning

confidence: 99%

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Divide-and-Conquer Linear-Scaling Quantum Chemical Computations

et al. 2023

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Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics

Gupta

Savytskyi

Coban

et al. 2023

Molecular Aspects of Medicine

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Protein–ligand interactions from a quantum fragmentation perspective: The case of the SARS-CoV-2 main protease interacting with α-ketoamide inhibitors

Genovese

Dawson

Nakajima

et al. 2023

The Journal of Chemical Physics

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We present a hybrid, multi-method, computational scheme for protein/ligand systems well suited to be used on modern and forthcoming massively parallel computing systems. The scheme relies on a multi-scale polarizable molecular modeling, approach to perform molecular dynamics simulations, and on an efficient Density Functional Theory (DFT) linear scaling method to post-process simulation snapshots. We use this scheme to investigate recent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2 virus. We assessed the reliability and the coherence of the hybrid scheme, in particular, by checking the ability of MM and DFT to reproduce results from high-end ab initio computations regarding such inhibitors. The DFT approach enables an a posteriori fragmentation of the system and an investigation into the strength of interaction among identified fragment pairs. We show the necessity of accounting for a large set of plausible protease/inhibitor conformations to generate reliable interaction data. Finally, we point out ways to further improve α-ketoamide inhibitors to more strongly interact with particular protease domains neighboring the active site.

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Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations

Cited by 6 publications

References 52 publications

Divide-and-Conquer Linear-Scaling Quantum Chemical Computations

Divide-and-Conquer Linear-Scaling Quantum Chemical Computations

Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics

Protein–ligand interactions from a quantum fragmentation perspective: The case of the SARS-CoV-2 main protease interacting with α-ketoamide inhibitors

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