Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

Using polarizable (AMOEBA) and non-polarizable (CHARMM) force fields, we compare the relative free-energy stability of two extreme conformations of the HIV-1 NCp7 nucleocapsid that had been previously experimentally advocated to prevail in solution. Using accelerated sampling techniques, we show that they differ in stability by no more than 0.75-1.9 kcal/mol depending on the reference protein sequence. While the extended form appears to be the most probable structure, both forms should thus coexist in water explaining the differing NMR findings.<br /

Tinker-HP: Accelerating Molecular Dynamics Simulations of Large Complex Systems with Advanced Point Dipole Polarizable Force Fields Using GPUs and Multi-GPU Systems

International audienceWe present the extension of the Tinker-HP package (Lagardere, et al. Chem. Sci. 2018, 9, 956−972) to the use of Graphics Processing Unit (GPU) cards to accelerate molecular dynamics simulations using polarizable many-body force fields. The new highperformance module allows for an efficient use of single-and multiple-GPU architectures ranging from research laboratories to modern supercomputer centers. After detailing an analysis of our general scalable strategy that relies on OPENACC and CUDA, we discuss the various capabilities of the package. Among them, the multiprecision possibilities of the code are discussed. If an efficient double precision implementation is provided to preserve the possibility of fast reference computations, we show that a lower precision arithmetic is preferred providing a similar accuracy for molecular dynamics while exhibiting superior performances. As Tinker-HP is mainly dedicated to accelerate simulations using new generation point dipole polarizable force field, we focus our study on the implementation of the AMOEBA model. Testing various NVIDIA platforms including 2080Ti, 3090, V100, and A100 cards, we provide illustrative benchmarks of the code for single-and multicards simulations on large biosystems encompassing up to millions of atoms. The new code strongly reduces time to solution and offers the best performances to date obtained using the AMOEBA polarizable force field. Perspectives toward the strong-scaling performance of our multinode massive parallelization strategy, unsupervised adaptive sampling and large scale applicability of the Tinker-HP code in biophysics are discussed. The present software has been released in phase advance on GitHub in link with the High Performance Computing community COVID-19 research efforts and is free for Academics (see https://github.com/ TinkerTools/tinker-hp)

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

International audienceWe 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

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

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 Mpr

Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface

Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is only stable at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy, since they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physico-chemical micro-environments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity

Interfacial Water Many-Body Effects Drive Structural Dynamics and Allosteric Interactions in SARS-CoV-2 Main Protease Dimerization Interface

Following our previous work (Chem. Sci. 2021, 12, 4889-4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 mu s) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is stable only at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy because they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physicochemical microenvironments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity

Tinker-HP: a Massively Parallel Molecular Dynamics Package for Multiscale Simulations of Large Complex Systems with Advanced Point Dipole Polarizable Force Fields

International audienceWe present Tinker-HP, a massively MPI parallel package dedicated to classical molecular dynamics (MD) and to multiscale simulations, using advanced polarizable force fields (PFF) encompassing distributed multipoles electrostatics. Tinker-HP is an evolution of the popular Tinker package code that conserves its simplicity of use and its reference double precision implementation for CPUs. Grounded on interdisciplinary efforts with applied mathematics, Tinker-HP allows for long polarizable MD simulations on large systems up to millions of atoms.We detail in the paper the newly developed extension of massively parallel 3D spatial decomposition to point dipole polarizable models as well as their coupling to efficient Krylov iterative and non-iterative polarization solvers. The design of the code allows the use of various computer systems ranging from laboratory workstations to modern petascale supercomputers with thousands of cores. Tinker-HP proposes therefore the first high-performance scalable CPU computing environment for the development of next generation point dipole PFFs and for production simulations. Strategies linking Tinker-HP to Quantum Mechanics (QM) in the framework of multiscale polarizable self-consistent QM/MD simulations are also provided. The possibilities, performances and scalability of the software are demonstrated via benchmarks calculations using the polarizable AMOEBA force field on systems ranging from large water boxes of increasing size and ionic liquids to (very) large biosystems encompassing several proteins as well as the complete satellite tobacco mosaic virus and ribosome structures. For small systems, Tinker-HP appears to be competitive with the Tinker-OpenMM GPU implementation of Tinker. As the system size grows, Tinker-HP remains operational thanks to its access to distributed memory and takes advantage of its new algorithmic enabling for stable long timescale polarizable simulations. Overall, a several thousand-fold acceleration over a single-core computation is observed for the largest systems. The extension of the present CPU implementation of Tinker-HP to other computational platforms is discussed

Restrictive use of Restraints and Delirium Duration in the Intensive Care Unit (R2D2-ICU): protocol for a French multicentre parallel-group open-label randomised controlled trial

Introduction Physical restraint (PR) is prescribed in patients receiving invasive mechanical ventilation in the intensive care unit (ICU) to avoid unplanned removal of medical devices. However, it is associated with an increased risk of delirium. We hypothesise that a restrictive use of PR, as compared with a systematic use, could reduce the duration of delirium in ICU patients receiving invasive mechanical ventilation.Methods and analysis The Restrictive use of Restraints and Delirium Duration in ICU (R2D2-ICU) study is a national multicentric, parallel-group, randomised (1:1) open-label, controlled, superiority trial, which will be conducted in 10 ICUs. A total of 422 adult patients requiring invasive mechanical ventilation for an expected duration of at least 48 hours and eligible for prescription of PR will be randomly allocated within 6 hours from intubation to either the restrictive PR use group or the systematic PR use group, until day 14, ICU discharge or death, whichever comes first. In both groups, PR will consist of the use of wrist straps. The primary endpoint will be delirium or coma-free days, defined as the number of days spent alive in the ICU without coma or delirium within the first 14 days after randomisation. Delirium will be assessed using the Confusion Assessment Method-ICU twice daily. Key secondary endpoints will encompass agitation episodes, opioid, propofol, benzodiazepine and antipsychotic drug exposure during the 14-day intervention period, along with a core outcome set of measures evaluated 90 days postrandomisation.Ethics and dissemination The R2D2-ICU study has been approved by the Comité de Protection des Personnes (CPP) ILE DE FRANCE III—PARIS (CPP19.09.06.37521) on June 10th, 2019). Participant recruitment started on 25 January 2021. Results will be published in international peer-reviewed medical journals and presented at conferences.Trial registration number NCT04273360