Comment on 'Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size'.

A recent molecular dynamics investigation into the stability of hemoglobin concluded that the unliganded protein is only stable in the T state when a solvent box is used in the simulations that is ten times larger than what is usually employed (El Hage et al., 2018). Here, we express three main concerns about that study. In addition, we find that with an order of magnitude more statistics, the reported box size dependence is not reproducible. Overall, no significant effects on the kinetics or thermodynamics of conformational transitions were observed

Predicting kinase inhibitor resistance: Physics-based and data-driven approaches.

Resistance to small molecule drugs often emerges in cancer cells, viruses, and bacteria as a result of the evolutionary pressure exerted by the therapy. Protein mutations that directly impair drug binding are frequently involved in resistance, and the ability to anticipate these mutations would be beneficial in drug development and clinical practice. Here, we evaluate the ability of three distinct computational methods to predict ligand binding affinity changes upon protein mutation for the cancer target Abl kinase. These structure-based approaches rely on first-principle statistical mechanics, mixed physics- and knowledge-based potentials, and machine learning, and were able to estimate binding affinity changes and identify resistant mutations with remarkable accuracy. We expect that these complementary approaches will enable the routine prediction of resistance-causing mutations in a variety of other target proteins

Free energy surfaces from nonequilibrium processes without work measurement

Recent developments in statistical mechanics have allowed the estimation of equilibrium free energies from the statistics of work measurements during processes that drive the system out of equilibrium. Here a different class of processes is considered, wherein the system is prepared and released from a nonequilibrium state, and no external work is involved during its observation. For such ``clamp-and-release'' processes, a simple strategy for the estimation of equilibrium free energies is offered. The method is illustrated with numerical simulations, and analyzed in the context of tethered single-molecule experiments.Comment: 15 pages, 3 figures (1 color); accepted to J. Chem. Phy

Mapping of sensitivity to oil spills in the Lithuanian Baltic Sea coast.

This research develops an integrated environmental assessment tool for Lithuanian coastal area that takes due account of the major oil spill risks posed by the D-6 oil drilling platform, vessel traffic in the south-eastern Baltic Sea, and operation of the Butinge oil terminal. The goal of this paper is to present an environmental sensitivity index (ESI) mapping approach based on four specific indexes: coastal features (ESIC), socio-economic aspects (ESISE), biological (ESIB) and fishery resources (ESIF). The relevant methodology approach was selected. The core dataset is provided by GIS-based environmental atlas updated with other relevant GIS data of Lithuanian coastal resources. Four ESI maps were developed and an overall environmental sensitivity index (OESI) map produced. Results indicate that in the case of an oil spill, two areas need to be prioritized due to their biologic and socio-economic resources: the 25 km long shoreline between the settlements of Nida-Juodkrante on the Curonian Spit (CS) and the mainland coast (MC) between the settlements Palanga and Sventoji

Comment on "Deficiencies in molecular dynamics simulation-based prediction of protein-DNA binding free energy landscapes"

Sequence-specific DNA binding transcription factors play an essential role in the transcriptional regulation of all organisms. The development of reliable in silico methods to predict the binding affinity landscapes of transcription factors thus promises to provide rapid screening of transcription factor specificities and, at the same time, yield valuable insight into the atomistic details of the interactions driving those specificities. Recent literature has reported highly discrepant results on the current ability of state-of-the-art atomistic molecular dynamics simulations to reproduce experimental binding free energy landscapes for transcription factors. Here, we resolve one important discrepancy by noting that in the case of alchemical free energy calculations involving base pair mutations, a common convention used in improving end point convergence of mixed potentials in fact can lead to erroneous results. The underlying cause for inaccurate double free energy difference estimates is specific to the particular implementation of the alchemical transformation protocol. Using the Gromacs simulation package, which is not affected by this issue, we obtain free energy landscapes in agreement with the experimental measurements; equivalent results are obtained for a small set of test cases with a modified version of the AMBER package. Our findings provide a consistent and optimistic outlook on the current state of prediction of protein-DNA binding free energy interactions using molecular dynamics simulations and an important precaution for appropriate end point handling in a broad range of free energy calculations

Morfologische, ecologische en governance principes voor ecodynamisch ontwerpen: toegespitst op de 'Bouwen met Natuur' pilots Friese IJsselmeerkust : building with nature, case Markermeer IJsselmeer, MIJ 4.2, Deliverable 1.6

Het concept ‘Bouwen met Natuur’ richt zich op gebiedsgerichte ontwerpprocessen langs kusten met het doel om de interactie tussen menselijke ingrepen en ecosysteem processen te vergroten. Het concept maakt maximaal gebruik van dynamiek van natuurlijke processen en van de inzet van bio@engineers bij de ontwikkeling van nieuwe kustlandschappen. De uitdaging bij ‘Bouwen met Natuur’ projecten is om een menselijke ambitie m.b.t. waterbouw te realiseren op een wijze die maximaal gebruik maakt van het ecosysteem en tevens dit ecosysteem versterkt. Het zoeken naar een win@win situatie voor zowel de menselijke waterbouwambitie als voor de natuurwaarden is dus iets anders dan natuur behouden die er is of nieuwe natuur ontwikkelen. Ook is het concept fundamenteel anders dan het compenseren van natuur die elders verloren gaat