Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

DFTB+, a software package for efficient approximate density functional theory based atomistic simulations.

DFTB+ is a versatile community developed open source software package offering fast and efficient methods for carrying out atomistic quantum mechanical simulations. By implementing various methods approximating density functional theory (DFT), such as the density functional based tight binding (DFTB) and the extended tight binding method, it enables simulations of large systems and long timescales with reasonable accuracy while being considerably faster for typical simulations than the respective ab initio methods. Based on the DFTB framework, it additionally offers approximated versions of various DFT extensions including hybrid functionals, time dependent formalism for treating excited systems, electron transport using non-equilibrium Green's functions, and many more. DFTB+ can be used as a user-friendly standalone application in addition to being embedded into other software packages as a library or acting as a calculation-server accessed by socket communication. We give an overview of the recently developed capabilities of the DFTB+ code, demonstrating with a few use case examples, discuss the strengths and weaknesses of the various features, and also discuss on-going developments and possible future perspectives.

Theoretical Investigation of Molecular and Electronic Structures of Buckminsterfullerene-Silicon Quantum Dot Systems.

Density functional theory (DFT) and density functional tight binding (DFTB) molecular dynamics (DFTB/MD) simulations of embedding and relaxation of buckminsterfullerene C60 molecules chemisorbed on (001) and (111) surfaces and inside bulk silicon lattice were performed. DFT calculations of chemisorbed fullerenes on both surfaces show that the C60 molecule deformation was very small and the C60 binding energies were roughly ∼4 eV. The charge analysis shows that the C60 molecule charges on (001) and (111) surfaces were between -2 and -3.5 electrons, respectively, that correlates well with the number of C-Si bonds linking the fullerene molecule and the silicon surface. DFT calculations of the C60 molecule inside bulk silicon confirm that the C60 molecule remains stable with the deformation energy values of between 11 and 15 eV for geometries with different C60 configurations. The formation of some C-Si bonds causes local silicon amorphization and corresponding electronic charge uptake on the embedded fullerene cages. Charge analysis confirms that a single C60 molecule can accept up to 20 excessive electrons that can be used in practice, wherein the main charge contribution is located on the fullerene's carbon atoms bonded to silicon atoms. These DFT calculations correlate well with DFTB/MD simulations of the embedding process. In this process, the C60 molecule was placed on the top of the Si(111) surface, and it was further exposed by a stream of silicon dimers, resulting in subsequent overgrowth by silicon.

Insights into carbon nanotube and graphene formation mechanisms from molecular simulations: a review.

The discovery of carbon nanotubes (CNTs) and graphene over the last two decades has heralded a new era in physics, chemistry and nanotechnology. During this time, intense efforts have been made towards understanding the atomic-scale mechanisms by which these remarkable nanostructures grow. Molecular simulations have made significant contributions in this regard; indeed, they are responsible for many of the key discoveries and advancements towards this goal. Here we review molecular simulations of CNT and graphene growth, and in doing so we highlight the many invaluable insights gained from molecular simulations into these complex nanoscale self-assembly processes. This review highlights an often-overlooked aspect of CNT and graphene formation-that the two processes, although seldom discussed in the same terms, are in fact remarkably similar. Both can be viewed as a 0D â†’ 1D â†’ 2D transformation, which converts carbon atoms (0D) to polyyne chains (1D) to a complete sp(2)-carbon network (2D). The difference in the final structure (CNT or graphene) is determined only by the curvature of the catalyst and the strength of the carbon-metal interaction. We conclude our review by summarizing the present shortcomings of CNT/graphene growth simulations, and future challenges to this important area.

Relative isomer abundance of fullerenes and carbon nanotubes correlates with kinetic stability.

A methodology to evaluate the kinetic stability of carbon nanostructures is presented based on the assumption of the independent and random nature of thermal vibrations. The kinetic stability is directly correlated to the cleavage probability for the weakest bond of a given nanostructure. The application of the presented method to fullerenes and carbon nanotubes yields clear correlation to their experimentally observed relative isomer abundances. The general and simple formulation of the method ensures its applicability to other nanostructures for which formation is controlled by kinetic factors.

[Sumbawanga eye camp follow-up study 2019]. / Sumbawanga Augencamp follow-up Studie 2019.

BACKGROUND: In 2019 the German Commission for the Prevention of Blindness (DKVB) held an eye camp in the Tanzanian town of Sumbawanga. For patients with mature cataracts and the ability to see light cateracts were treated by manual small incision cataract surgery (MSICS). For the first time in this camp the quality of the results of the cataract operations was measured. OBJECTIVE: The quality of the cataract operations is presented and the results were assessed in the context of the guidelines of the World Health Organization (WHO). METHODS: Those patients who had a cataract operation in the first week were examined during the second week with respect to the parameters vision, refraction, split lamp microscopic findings, results and complications after surgery. The results were retrospectively evaluated and compared with the guidelines of the WHO. RESULTS: A total of 42 postoperative patients from the eye camp could be examined within 5-9 days after cataract sugery. The following parameters were found: median postoperative visual acuity 0.26, spherical equivalent -2.82 dpt, astigmatism -2.2 dpt, axis 113°. Visual acuity >0.3 in 14.2% (WHO 80%), vision 0.1-0.3 in 62% (WHO 15%), vision <0.1 in 23.8% (WHO 5%). Prolonged healing time and intraocular irritation in 29% of the cases. CONCLUSION: Although the vision improved, the results are sobering when taken in the context of the WHO guidelines. The postoperative refraction showed a myopic shift and an high level of astigmatism. The reasons are manifold: ocular comorbidities, limited diagnostic and therapeutic possibilities in a nonclinical setting. Other factors are the kind of training of the staff in the camp, the difficult circumstances and advanced findings. Consideration of the results of this study is imperative to be able to measure the quality of the work and to create the potential to make future improvements.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

Indirect Intersystem Crossing (S1 → T3/T2 → T1) Promoted by the Jahn-Teller Effect in Cycloparaphenylenes.

Vibronic-coupling effects play a key role for excited-state charge- and energy-transfer processes in organic molecular systems. Here, we demonstrate how the Jahn-Teller effect in triplet excited states of highly symmetric cycloparaphenylenes triggers an indirect intersystem crossing deactivation pathway. Strong Jahn-Teller distortion in the doubly degenerate second excited triplet state (T2) brings the molecular system energetically close to the lowest triplet state (T1), thereby opening the possibility for an extremely rapid internal conversion. Quantum dynamics simulations reveal an initial T2 → T1 population decay within 50 fs. Experimental observation of size-dependent intersystem crossing rates of cycloparaphenylenes is explained based on the proposed S1 → T3/T2 → T1 mechanism.

Quantum chemical prediction of reaction pathways and rate constants for dissociative adsorption of CO(x) and NO(x) on the graphite (0001) surface.

We present predictions of reaction rate constants for dissociative adsorption reactions of CO(x) (x = 1, 2) and NO(x) (x = 1, 2) molecules on the basal graphite (0001) surface based on potential energy surfaces (PES) obtained by the integrated ONIOM(B3LYP:DFTB-D) quantum chemical hybrid approach with dispersion-augmented density functional tight binding (DFTB-D) as low level method. Following an a priori methodology developed in a previous investigation of water dissociative adsorption reactions on graphite, we used a C(94)H(24) dicircumcoronene graphene slab as model system for the graphite surface in finite-size molecular structure investigations, and single adsorbate molecules reacting with the pristine graphene sheet. By employing the ONIOM PES information in RRKM theory we predict reaction rate constants in the temperature range between 1,000 and 5,000 K. We find that among CO(x) and NO(x) adsorbate species, the dissociative adsorption reactions of CO(2) and both radical species NO and NO(2) are likely candidates as a cause for high temperature oxidation and erosion of graphite (0001) surfaces, whereas reaction with CO is not likely to lead to long-lived surface defects. High temperature quantum chemical molecular dynamics simulations (QM/MD) at T = 5,000 K using on-the-fly DFTB-D energies and gradients confirm the results of our PES study.

Mechanisms of the reactions of W AND W+ with H2O: computational studies.

The mechanism of the reactions of W and W(+) with the water molecule have been studied for several lower-lying electronic states of tungsten centers at the CCSD(T)/6-311G(d,p)+SDD and B3LYP/6-31G(d,p)+SDD levels of theory. It is shown that these reactions are essentially multistate processes, during which lower-lying electronic states of the systems cross several times. They start with the formation of initial prereaction M(H(2)O) complexes with M-H(2)O bonding energies of 9.6 and 48.2 kcal/mol for M = W and W(+), followed by insertion of the metal center into an O-H bond with 20.0 and 53.3 kcal/mol barriers for neutral and cationic systems, respectively. The overall process of M + H(2)O --> t-HM(OH) is calculated to be highly exothermic, 48.4 and 48.8 kcal/mol for M = W and W(+). From the HM(OH) intermediate the reaction may proceed via several different channels, among which the stepwise HM(OH) --> HMO + H --> (H)(2)MO and concerted HM(OH) --> (H)(2)MO pathways are more favorable and can compete (energetically) with each other. For the neutral system (M = W), the concerted process is the most favorable, whereas for the charged system (M = W(+)), the stepwise pathway is slightly more favorable. From the energetically most favorable intermediate (H)(2)MO the reactions proceed via H(2)-molecule formation with a 53.1 kcal/mol activation barrier for the neutral system. For the cationic system, H-H formation and dissociation is an almost barrierless process. The overall reaction of W and W(+) with the water molecule leading to H(2) + MO formation is found to be exothermic by 48.2 and 39.8 kcal/mol, respectively. In the gas phase with the collision-less conditions the reactions W((7)S) + H(2)O --> H(2) + WO((3)Sigma(+)), and W(+)((6)D) + H(2)O --> H(2) + WO(+)((4)Sigma(+)) are expected to proceed via a 10.4 and 5.1 kcal/mol overall energy barrier corresponding to the first O-H dissociation at the TS1. On the basis of these PESs, we predict kinetic rate constants for the reactions of W and W(+) with H(2)O.

[Topical anesthesia as routine procedure in cataract surgery -- evaluation of pain and complications in 1010 cases]. / Topische Anästhesie als Routineverfahren bei der Kataraktchirurgie -- Schmerzbewertung und Komplikationen bei einem grösseren Patientenkollektiv.

BACKGROUND: The number of cataract surgeries using topical anesthesia has increased continuously in the United States in the last years. Over 60 % of all cataract surgeons accept this form of anesthesia as first choice in cataract surgery. Surgeons in German-speaking countries still prefer injection anesthesia. Patient pain and complications during cataract surgery under topical anesthesia were recorded in 1010 cases to find out if topical anesthesia will become established as a routine procedure in Germany. PATIENTS AND METHODS: Cataract surgery was performed as a routine procedure by two surgeons as phacoemulsification with implantation of a foldable posterior chamber lens. Preoperative tetracaine drops were applied three times. Additionally, non-preserved lidocaine 1 % was injected into the anterior chamber. Patients assessed pain intensity by checking off a visual analogue scale 1 to 10. Intra-operative complications were recorded by the surgeons. The level of pain, intra-operative complications, age of patients, duration of surgery and type of implanted intraocular lens were analyzed by descriptive statistical methods. RESULTS: The evaluation of intra-operative pain showed an overall mean pain score of 1.62. The pain was described as minor and light by 98.8 % of all patients. Complications happened in not more than 0.5 % of the cases related to the single complication. Complications did not necessarily lead to a higher rating of pain. CONCLUSIONS: Topical anesthesia using tetracaine drops with adjunctive intracameral injection of non-preserved lidocaine 1 % is a safe and efficient form of anesthesia in phacoemulsification and is well tolerated by patients. According to the patients' positive assessment and the low rate of complications, drop anesthesia is well suited for clinical routine.

Water clusters on graphite: methodology for quantum chemical a priori prediction of reaction rate constants.

The properties, interactions, and reactions of cyclic water clusters (H(2)O)(n=1-5) on model systems for a graphite surface have been studied using pure B3LYP, dispersion-augmented density functional tight binding (DFTB-D), and integrated ONIOM(B3LYP:DFTB-D) methods. Coronene C(24)H(12) as well as polycircumcoronenes C(96)H(24) and C(216)H(36) in monolayer, bilayer, and trilayer arrangements were used as model systems to simulate ABA bulk graphite. Structures, binding energies, and vibrational frequencies of water clusters on mono- and bilayer graphite models have been calculated, and structural changes and frequency shifts due to the water cluster-graphite interactions are discussed. ONIOM(B3LYP:DFTB-D) with coronene and water in the high level and C(96)H(24) in the low level mimics the effect of extended graphite pi-conjugation on the water-graphite interaction very reasonably and suggests that water clusters only weakly interact with graphite surfaces, as suggested by the fact that water is an excellent graphite lubricant. We use the ONIOM(B3LYP:DFTB-D) method to predict rate constants for model pathways of water dissociative adsorption on graphite. Quantum chemical molecular dynamics (QM/MD) simulations of water clusters and water addition products on the C(96)H(24) graphite model are presented using the DFTB-D method. A three-stage strategy is devised for a priori investigations of high temperature corrosion processes of graphite surfaces due to interaction with water molecules and fragments.

Prediction of the post-comatose motor function by motor evoked potentials obtained in the acute phase of traumatic and non-traumatic coma.

OBJECTIVE: To define the value of electrically elicited motor evoked potentials (MEP), obtained during the initial phase of the coma, for correct prediction of the post-coma motor status. METHODS: Fifty-two patients were investigated by MEP within 72 hours after onset of the coma. It was the aim to correlate the MEP findings to the motor function two months after coma onset. RESULTS: Three patients with normal MEP showed no post-coma motor deficit. In 21 patients, a bilateral, symmetric prolongation of the central motor conduction time (CMCT) was registered. Eighteen of these 21 patients (86%) showed a normal post-coma motor status. In 28 patients, unilaterally absent evoked potential, or unilaterally prolonged CMCT, or bilaterally prolonged CMCT with significant difference in each hemisphere were observed. A post-coma contralateral paresis was found in 25 of these 28 patients (89%). That paresis was functionally important in 15 patients (54%) and functionally unimportant in 13 patients (46%). CONCLUSION: We identified certain MEP patterns (unilateral extinction of the evoked potential, unilateral, bilateral prolongation of the CMCT with significant "side" difference), which indicated a pyramidal tract lesion and a post-coma motor deficit with an accuracy of 89%. This refers to the motor results, which may not be the final post-coma motor results which are usually assessed six months after the coma onset. The MEP changes did not allow one to predict the severity of the paresis. The accuracy of prediction of a motor deficit increased from the MEP finding of unilaterally prolonged CMCT to the MEP finding of unilateral extinction of the potential. The most common finding, bilateral central motor slowing without significant "side" difference, did not indicate a post-coma paresis in 86%, leading to the assumption, that bilateral, symmetrical prolongation of the CMCT was not caused by lesions of the descending motor pathways, but by the drugs administered for treating the comatose patient. In conclusion, MEP allows one to predict the presence of a post-coma motor deficit with a high degree of accuracy already in the initial phase of coma, but MEP fails to predict the severity of that deficit.