MiMiC: Multiscale Modeling in Computational Chemistry

Bolnykh, Viacheslav; Olsen, Jógvan Magnus Haugaard; Meloni, Simone; Bircher, Martin Peter; Ippoliti, Emiliano; Carloni, Paolo; Röthlisberger, Ursula

doi:10.3389/fmolb.2020.00045

Cited by 8 publications

(3 citation statements)

References 23 publications

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“…A representative snapshot of the low conductance mode observed during the force field based MD simulations served as the starting structure for our QM/MM simulations. The MiMiC interface ,, was used to couple GROMACS and CPMD . The QM part comprises a calcium ion at Site 1 together with its first hydration shell and was treated with plane-wave and pseudopotential based Density Functional Theory (DFT), while the MM part of the system was described by the same force field as in the classical MD simulations.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

Schackert

Biedermann

Abdolvand

et al. 2023

J. Chem. Inf. Model.

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The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are neurotransmitter-activated cation channels ubiquitously expressed in vertebrate brains. The regulation of calcium flux through the channel pore by RNA-editing is linked to synaptic plasticity while excessive calcium influx poses a risk for neurodegeneration. Unfortunately, the molecular mechanisms underlying this key process are mostly unknown. Here, we investigated calcium conduction in calcium-permeable AMPAR using Molecular Dynamics (MD) simulations with recently introduced multisite force-field parameters for Ca 2+ . Our calculations are consistent with experiment and explain the distinct calcium permeability in different RNA-edited forms of GluA2. For one of the identified metal binding sites, multiscale Quantum Mechanics/Molecular Mechanics (QM/ MM) simulations further validated the results from MD and revealed small but reproducible charge transfer between the metal ion and its first solvation shell. In addition, the ion occupancy derived from MD simulations independently reproduced the Ca 2+ binding profile in an X-ray structure of an NaK channel mimicking the AMPAR selectivity filter. This integrated study comprising X-ray crystallography, multisite MD, and multiscale QM/MM simulations provides unprecedented insights into Ca 2+ permeation mechanisms in AMPARs, and paves the way for studying other biological processes in which Ca 2+ plays a pivotal role.

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Section: Methodsmentioning

confidence: 99%

Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

Schackert

Biedermann

Abdolvand

et al. 2023

J. Chem. Inf. Model.

Self Cite

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“…7 Exascale calculations however remain one of the major challenges in molecular simulations ( Hospital et al, 2015 ; Páll et al, 2015 ). Recent advances in massively scalable QM/MM codes, such as that developed in Juelich in collaboration with European universities ( Olsen et al, 2019 ; Bolnykh et al, 2020a ) (see Supplementary Material S7 ) and their successful applications to predict free energy landscapes associated with biological processes ( Bolnykh et al, 2020a ; Chiariello et al, 2020 ) brings us to suggest that in a not-too-far future QM/MM calculations may exploit the unprecedented power of exascale computing for direct MD simulations of ligand (un)binding ( Bolnykh et al, 2020b , Bolnykh et al, 2021 ).…”

Section: Perspectives: From Polarizable Force Fields To Qm/mm Calcula...mentioning

confidence: 99%

Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective

Ahmad

Rizzi

Capelli

et al. 2022

Front. Mol. Biosci.

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The dissociation rate (koff) associated with ligand unbinding events from proteins is a parameter of fundamental importance in drug design. Here we review recent major advancements in molecular simulation methodologies for the prediction ofkoff. Next, we discuss the impact of the potential energy function models on the accuracy of calculatedkoffvalues. Finally, we provide a perspective from high-performance computing and machine learning which might help improve such predictions.

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“…Recent advances in massively scalable QM/MM codes, such as that developed in Juelich in collaboration with European universities (Olsen et al, 2019;Bolnykh et al, 2020a) (see Supplementary Material S7) and their successful applications to predict free energy landscapes associated with biological processes (Bolnykh et al, 2020a;Chiariello et al, 2020) brings us to suggest that in a not-too-far future QM/MM calculations may exploit the unprecedented power of exascale computing for direct MD simulations of ligand (un)binding (Bolnykh et al, 2020b, Bolnykh et al, 2021.…”

Section: Parallel Computing In Dft-based Qm/mmmentioning

confidence: 99%

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MiMiC: Multiscale Modeling in Computational Chemistry

Cited by 8 publications

References 23 publications

Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective

DataSheet1.PDF

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