Best bang for your buck: GPU nodes for GROMACS biomolecular simulations

The molecular dynamics simulation package GROMACS runs efficiently on a wide variety of hardware from commodity workstations to high performance computing clusters. Hardware features are well exploited with a combination of SIMD, multi-threading, and MPI-based SPMD/MPMD parallelism, while GPUs can be used as accelerators to compute interactions offloaded from the CPU. Here we evaluate which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most economical way. We have assembled and benchmarked compute nodes with various CPU/GPU combinations to identify optimal compositions in terms of raw trajectory production rate, performance-to-price ratio, energy efficiency, and several other criteria. Though hardware prices are naturally subject to trends and fluctuations, general tendencies are clearly visible. Adding any type of GPU significantly boosts a node's simulation performance. For inexpensive consumer-class GPUs this improvement equally reflects in the performance-to-price ratio. Although memory issues in consumer-class GPUs could pass unnoticed since these cards do not support ECC memory, unreliable GPUs can be sorted out with memory checking tools. Apart from the obvious determinants for cost-efficiency like hardware expenses and raw performance, the energy consumption of a node is a major cost factor. Over the typical hardware lifetime until replacement of a few years, the costs for electrical power and cooling can become larger than the costs of the hardware itself. Taking that into account, nodes with a well-balanced ratio of CPU and consumer-class GPU resources produce the maximum amount of GROMACS trajectory over their lifetime

More Bang for Your Buck: Improved use of GPU Nodes for GROMACS 2018

We identify hardware that is optimal to produce molecular dynamics trajectories on Linux compute clusters with the GROMACS 2018 simulation package. Therefore, we benchmark the GROMACS performance on a diverse set of compute nodes and relate it to the costs of the nodes, which may include their lifetime costs for energy and cooling. In agreement with our earlier investigation using GROMACS 4.6 on hardware of 2014, the performance to price ratio of consumer GPU nodes is considerably higher than that of CPU nodes. However, with GROMACS 2018, the optimal CPU to GPU processing power balance has shifted even more towards the GPU. Hence, nodes optimized for GROMACS 2018 and later versions enable a significantly higher performance to price ratio than nodes optimized for older GROMACS versions. Moreover, the shift towards GPU processing allows to cheaply upgrade old nodes with recent GPUs, yielding essentially the same performance as comparable brand-new hardware.Comment: 41 pages, 13 figures, 4 tables. This updated version includes the following improvements: - most notably, added benchmarks for two coarse grain MARTINI systems VES and BIG, resulting in a new Figure 13 - fixed typos - made text clearer in some places - added two more benchmarks for MEM and RIB systems (E3-1240v6 + RTX 2080 / 2080Ti

The allosteric lever: towards a principle of specific allosteric response

Allostery, the phenomenon by which the perturbation of a molecule at one site alters its behavior at a remote functional site, enables control over biomolecular function. Allosteric modulation is a promising avenue for drug discovery and is employed in the design of mechanical metamaterials. However, a general principle of allostery, i.e. a set of quantitative and transferable "ground rules", remained elusive. It is neither a set of structural motifs nor intrinsic motions. Focusing on elastic network models, we here show that an allosteric lever--a mode-coupling pattern induced by the perturbation--governs the directional, source-to-target, allosteric communication: a structural perturbation of an allosteric site couples the excitation of localized hard elastic modes with concerted long range soft-mode relaxation. Perturbations of non-allosteric sites instead couple hard and soft modes uniformly. The allosteric response is shown to be generally non-linear and non-reciprocal, and allows for minimal structural distortions to be efficiently transmitted to specific changes at distant sites. Allosteric levers exist in proteins and "pseudoproteins"--networks designed to display an allosteric response. Interestingly, protein sequences that constitute allosteric transmission channels are shown to be evolutionarily conserved. To illustrate how the results may be applied in drug design, we use them to successfully predict known allosteric sites in proteins

A litmus test for classifying recognition mechanisms of transiently binding proteins

Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin’s paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks

After the honeymoon: The Obama effect on political attitudes and participation

My dissertation takes a mixed-methods approach to investigating the possibility of a lasting Obama Effect on the political attitudes and behaviors of Obama supporters from 2008. Defining the Obama Effect as the extraordinary enthusiasm surrounding Barack Obama’s 2008 campaign, I argue that a short term Obama Effect was clearly present in 2008 based on Obama’s electoral success, fundraising prowess, and ability to inspire volunteerism, as well as on the historic nature of his candidacy. But I ask, was it a lasting effect? My quantitative analyses—built upon panel survey data from the American National Election Studies—suggest little evidence of a lasting campaign effect that was positive and/or unique to Obama supporters. With regard to attitudes and behaviors such as political interest, political efficacy, or attendance of political events, Obama supporters often showed relative declines or stagnation over time when compared to nonsupporters or supporters of previous presidents. My qualitative analysis—based upon interviews with 30 former volunteers from the 2008 Obama campaign—does, however, indicated that the Obama Effect had a deep and lasting impact on his most enthusiastic support base, those who volunteered for his campaign. Many former Obama volunteers remained highly interested, civically engaged, and continually inspired as a result of their activism for the 2008 Obama campaign. In sum, I conclude that while that campaign may not have had its desired transformational effect on the broader American electorate, it did produce a positive and indeed a lasting impact on its most enthusiastic supporters

A litmus test for classifying recognition mechanisms of transiently binding proteins

Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin’s paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks

Prolonged antibiotic prophylaxis after pancreatoduodenectomy:systematic review and meta-analysis

Background: Previous studies have reported conflicting results of prolonged antibiotic prophylaxis on infectious complications after pancreatoduodenectomy. This study evaluated the effect of prolonged antibiotics on surgical-site infections (SSIs) after pancreatoduodenectomy. Methods: A systematic review and meta-analysis was undertaken of SSIs in patients with perioperative (within 24 h) versus prolonged antibiotic (over 24 h) prophylaxis after pancreatoduodenectomy. SSIs were classified as organ/space infections or superficial SSI within 30 days after surgery. ORs were calculated using a Mantel–Haenszel fixed-effect model.Results:Ten studies were included in the qualitative analysis, of which 8 reporting on 1170 patients were included in the quantitative analysis. The duration of prolonged antibiotic prophylaxis varied between 2 and 10 days after surgery. Four studies reporting on 782 patients showed comparable organ/space infection rates in patients receiving perioperative and prolonged antibiotics (OR 1.35, 95 per cent c.i. 0.94 to 1.93). However, among patients with preoperative biliary drainage (5 studies reporting on 577 patients), organ/space infection rates were lower with prolonged compared with perioperative antibiotics (OR 2.09, 1.43 to 3.07). Three studies (633 patients) demonstrated comparable superficial SSI rates between patients receiving perioperative versus prolonged prophylaxis (OR 1.54, 0.97 to 2.44), as well as in patients with preoperative biliary drainage in 4 studies reporting on 431 patients (OR 1.60, 0.89 to 2.88). Conclusion: Prolonged antibiotic prophylaxis is associated with fewer organ/space infection in patients who undergo preoperative biliary drainage. However, the optimal duration of antibiotic prophylaxis after pancreatoduodenectomy remains to be determined and warrants confirmation in an RCT.</p

Is TEA an inhibitor for human Aquaporin-1?

Excessive water uptake through aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel aquaporin-1 by a combined molecular docking and molecular dynamics simulation approach. The binding site identified from docking studies was independently confirmed with an unbiased molecular dynamics simulation of an aquaporin tetramer embedded in a lipid membrane, surrounded by a 100-mM tetraethylammonium solution in water. A third independent assessment of the binding site was obtained by umbrella sampling simulations. These simulations, in addition, revealed a binding affinity of more than 17 kJ/mol, corresponding to an IC50 value of << 3 mM. Finally, we observed in our simulations a 50% reduction of the water flux in the presence of TEA, in agreement with water permeability measurements on aquaporin expressed in oocytes. These results confirm TEA as a putative lead for an aquaporin-1 inhibitor