scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2020 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henri Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
The Other ◽  
Conformational Space ◽  
Processing Unit ◽  
X Rays ◽  
Main Protease ◽  
The Stability ◽  
Apo State

We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease (Mpro) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2020 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henry Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
The Other ◽  
Conformational Space ◽  
Processing Unit ◽  
X Rays ◽  
Main Protease ◽  
The Stability ◽  
Apo State

We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease (Mpro) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2020 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henri Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
The Other ◽  
Conformational Space ◽  
Processing Unit ◽  
X Rays ◽  
Main Protease ◽  
The Stability ◽  
Apo State

We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease (Mpro) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2020 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henry Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
The Other ◽  
Conformational Space ◽  
Processing Unit ◽  
X Rays ◽  
Main Protease ◽  
The Stability ◽  
Apo State

We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease (Mpro) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2020 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henry Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
The Other ◽  
Conformational Space ◽  
Processing Unit ◽  
X Rays ◽  
Main Protease ◽  
The Stability ◽  
Apo State

We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease (Mpro) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2020 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henri Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
The Other ◽  
Conformational Space ◽  
Processing Unit ◽  
X Rays ◽  
Main Protease ◽  
The Stability ◽  
Apo State

We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease (Mpro) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

scholarly journals High-resolution mining of the SARS-CoV-2 main protease conformational space: supercomputer-driven unsupervised adaptive sampling

2021 ◽  
Author(s):  
Théo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henri Jolly ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Adaptive Sampling ◽  
Force Fields ◽  
Sampling Strategy ◽  
Md Simulations ◽  
Conformational Space ◽  
Many Body ◽  
Polarizable Force Fields ◽  
Main Protease

We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs).

scholarly journals High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

2021 ◽  
Author(s):  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Olivier Adjoua ◽  
Dina El Ahdab ◽  
Luc-Henri Jolly ◽  
...  
Keyword(s):  
High Resolution ◽  
Adaptive Sampling ◽  
Dipole Moments ◽  
Sampling Strategy ◽  
Md Simulations ◽  
Conformational Space ◽  
Many Body ◽  
Main Protease ◽  
Comparison Results ◽  
Wide Range

We provide an unsupervised adaptive sampling strategy capable of producing microseconds-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFF). The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within a selective process to achieve sufficient phase-space sampling. Accurate statistical properties can be obtained through reweighting. Within this highly parallel setup, the Tinker--HP package can be powered by an arbitrary large number of GPUs on supercomputers, reducing exploration time from years to days. This approach is used to tackle the urgent modeling problem of the SARS--CoV--2 Main Protease (Mpro) producing more than 38 microseconds of all-atom simulations of its apo, ligand-free, dimer using the high-resolution AMOEBA PFF. A first 15.14 microseconds simulation (physiological pH) is compared to available non--PFF long-timescale simulation data. A detailed clustering analysis exhibits striking differences between FFs, AMOEBA showing a richer conformational space. Focusing on key structural markers related to the oxyanion hole stability, we observe an asymmetry between protomers. One of them appears less structured resembling the experimentally inactive monomer for which a 6 microseconds simulation was performed as a basis of comparison. Results highlight the plasticity of Mpro active site. The C--terminal end of its less structured protomer is shown to oscillate between several states, being able to interact with the other protomer, potentially modulating its activity. Active and distal sites volumes are found to be larger in the most active protomer within our AMOEBA simulations compared to non-PFFs as additional cryptic pockets are uncovered. A second 17 microseconds AMOEBA simulation is performed with protonated His172 residues mimicking lower pH. Data show the protonation impact on the destructuring of the oxyanion loop. We finally analyze the solvation patterns around key histidine residues. The confined AMOEBA polarizable water molecules are able to explore a wide range of dipole moments, going beyond bulk values, leading to a water molecule counts consistent with experiment. Results suggest that the use of PFFs could be critical in drug discovery to accurately model the complexity of the molecular interactions structuring Mpro

Uniformity of Magnification from Different Electron Microscopes

1967 ◽  
Vol 25 ◽  
pp. 32-33
Author(s):  
Godfrey C. Hoskins ◽  
V. Williams ◽  
V. Allison
Keyword(s):  
Diffraction Grating ◽  
The Other ◽  
Carbon Replica ◽  
Electron Microscopes ◽  
The Stability

The method demonstrated is an adaptation of a proven procedure for accurately determining the magnification of light photomicrographs. Because of the stability of modern electrical lenses, the method is shown to be directly applicable for providing precise reproducibility of magnification in various models of electron microscopes.A readily recognizable area of a carbon replica of a crossed-line diffraction grating is used as a standard. The same area of the standard was photographed in Phillips EM 200, Hitachi HU-11B2, and RCA EMU 3F electron microscopes at taps representative of the range of magnification of each. Negatives from one microscope were selected as guides and printed at convenient magnifications; then negatives from each of the other microscopes were projected to register with these prints. By deferring measurement to the print rather than comparing negatives, correspondence of magnification of the specimen in the three microscopes could be brought to within 2%.

An Analysis of Dissociation of Molecules in a High Resolution Electron Microscope

1973 ◽  
Vol 31 ◽  
pp. 486-487
Author(s):  
Mihir Parikh
Keyword(s):  
Electron Microscope ◽  
High Resolution ◽  
Cross Sections ◽  
Resolving Power ◽  
Peak Intensity ◽  
Molecular Film ◽  
Resolution Electron ◽  
Dissociation Cross Section ◽  
High Resolution Electron Microscope ◽  
The Stability

It is well known that the resolution of bio-molecules in a high resolution electron microscope depends not just on the physical resolving power of the instrument, but also on the stability of these molecules under the electron beam. Experimentally, the damage to the bio-molecules is commo ly monitored by the decrease in the intensity of the diffraction pattern, or more quantitatively by the decrease in the peaks of an energy loss spectrum. In the latter case the exposure, EC, to decrease the peak intensity from IO to I’O can be related to the molecular dissociation cross-section, σD, by EC = ℓn(IO /I’O) /ℓD. Qu ntitative data on damage cross-sections are just being reported, However, the microscopist needs to know the explicit dependence of damage on: (1) the molecular properties, (2) the density and characteristics of the molecular film and that of the support film, if any, (3) the temperature of the molecular film and (4) certain characteristics of the electron microscope used

Computer-Controlled Hrem Alignment Using Automated Diffractogram Analysis

1990 ◽  
Vol 48 (1) ◽  
pp. 532-533
Author(s):  
G.Y. Fan ◽  
O.L. Krivanek
Keyword(s):  
Electron Microscope ◽  
High Resolution ◽  
The Other ◽  
Full Information ◽  
Resolution Electron ◽  
Skilled Operator ◽  
Automatic Alignment ◽  
High Resolution Electron Microscope ◽  
Computer Controlled ◽  
Recorded Image

Full alignment of a high resolution electron microscope (HREM) requires five parameters to be optimized: the illumination angle (beam tilt) x and y, defocus, and astigmatism magnitude and orientation. Because neither voltage nor current centering lead to the correct illumination angle, all the adjustments must be done on the basis of observing contrast changes in a recorded image. The full alignment can be carried out by a computer which is connected to a suitable image pick-up device and is able to control the microscope, sometimes with greater precision and speed than even a skilled operator can achieve. Two approaches to computer-controlled (automatic) alignment have been investigated. The first is based on measuring the dependence of the overall contrast in the image of a thin amorphous specimen on the relevant parameters, the other on measuring the image shift. Here we report on our progress in developing a new method, which makes use of the full information contained in a computed diffractogram.

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