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.

The effects of a water polo game on the blood redox status of male water polo players.

AIM: The purpose of this study was to examine the effects of a real water polo game on the oxidative stress and antioxidants markers of male water polo players. The importance of this study is that it is the first to examine the oxidative stress and antioxidants markers after a water polo game, considering the specific and high demands of the latter. METHODS: Twelve players (25.8±3.7 years) were assessed from two teams. The oxidative stress and antioxidants markers which were measured were TBARS, Protein Carbonyls, GSH and GSSG, Total Antioxidant Capacity (TAC) and Catalase. RESULTS: An increase was found after the game for TBARS, for catalase, for GSH, and GSSG. Protein Carbonyls, TAC and the GSH/GSSG ratio did not change significantly. CONCLUSION: The water polo game was found to be a strong stimulus for oxidative stress, while alterations seem to appear for the antioxidant capability, as indicated by increase of catalase and GSH. The increase of the latter is controversial to the usual effect post exercise. A possible explanation for this effect could be the activation of GSH synthesis in order to meet the increased needs for antioxidant protection. Also, it should be considered that blood samples were taken 10-20 min. after the game, so it is possible that in well-trained subjects, this time period is enough for the conversion of GSSG back to GSH. Yet, it can be stated that, despite the enhanced antioxidant defense of the players, oxidative stress could not be prevented.

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.

Nematic-isotropic transition with quenched disorder.

Nematic elastomers do not show the discontinuous, first-order, phase transition that the Landau-De Gennes mean field theory predicts for a quadrupolar ordering in three dimensions. We attribute this behavior to the presence of network crosslinks, which act as sources of quenched orientational disorder. We show that the addition of weak random anisotropy results in a singular renormalization of the Landau-De Gennes expression, adding an energy term proportional to the inverse quartic power of order parameter Q. This reduces the first-order discontinuity in Q. For sufficiently high disorder strength the jump disappears altogether and the phase transition becomes continuous, in some ways resembling the supercritical transitions in external field.

Echocardiographic characteristics in adolescent junior male athletes of different sport events.

The purpose of this study was to examine the effects of different sport activities on cardiac adaptation. Echocardiographic data of 137 athletes and 21 non-athletes were measured and compared in two age groups 15-16 and 17-18 years of age. Athletes belonged into three groups according to their sports activity (endurance events, power athletes, ball game players). The observed variables were related to body size by indices in which the exponents of the numerator and the denominator were matched. Left ventricular hypertrophy was manifest in all athletic groups. Power athletes had the largest mean left ventricular wall thickness (LVWTd) in both age groups. In the older age group differences between the athletic groups were smaller, but the endurance and power athletes had significantly higher wall thickness. Left ventricular internal diameter (LVIDd) was the largest in the endurance athletes, while mean relative muscle mass (LVMM) was the largest in the power athletes. LVMM of the older endurance athletes was significantly larger. Muscular quotient (MQ) was the highest in the endurance athletes; in the 17-18-year group there was no inter-event difference. Bradycardia was most manifest in the endurance athletes and ball game players, power athletes had higher resting heart rates than non-athletic subjects. It can be inferred that endurance training induces firstly an enlargement of the left ventricle what is then followed by an increase of muscle mass. In the studied functional and regulatory parameters no difference was found between the athletic and non-athletic groups.