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

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

Observation of negative differential conductance in a reverse-biased Ni/Ge Schottky diode

We report the experimental observation of negative differential conductance in a Ni/Ge Schottky diode. With the aid of theoretical models and numerical simulation we show that, at reverse bias, electons tunnel into the high electric field of the depletion region. This scatters the electrons into the upper valley of the Ge conduction band, which has a lower mobility. The observed negative differential conductance is hence attributed to the transferred-electron effect. This shows that Schottky contacts can be used to create hot electrons for transferred-electron devices

Speed limits for quantum gates in multi-qubit systems

We use analytical and numerical calculations to obtain speed limits for various unitary quantum operations in multiqubit systems under typical experimental conditions. The operations that we consider include single-, two-, and three-qubit gates, as well as quantum-state transfer in a chain of qubits. We find in particular that simple methods for implementing two-qubit gates generally provide the fastest possible implementations of these gates. We also find that the three-qubit Toffoli gate time varies greatly depending on the type of interactions and the system's geometry, taking only slightly longer than a two-qubit controlled-NOT (CNOT) gate for a triangle geometry. The speed limit for quantum-state transfer across a qubit chain is set by the maximum spin-wave speed in the chain.Comment: 7 pages (two-column), 2 figures, 2 table

Single-channel behavior of heteromeric α1β glycine receptors: an attempt to detect a conformational change before the channel opens

The α1β heteromeric receptors are likely to be the predominant synaptic form of glycine receptors in the adult. Their activation mechanism was investigated by fitting putative mechanisms to single-channel recordings obtained at four glycine concentrations (10-1000 µM) from rat {alpha}1{beta} receptors, expressed in human embryonic kidney 293 cells. The adequacy of each mechanism, with its fitted rate constants, was assessed by comparing experimental dwell time distributions, open-shut correlations, and the concentration-open probability (Popen) curve with the predictions of the model. A good description was obtained only if the mechanism had three glycine binding sites, allowed both partially and fully liganded openings, and predicted the presence of open-shut correlations. A strong feature of the data was the appearance of an increase in binding affinity as more glycine molecules bind, before the channel opens. One interpretation of this positive binding cooperativity is that binding sites interact, each site sensing the state of ligation of the others. An alternative, and novel, explanation is that agonist binding stabilizes a higher affinity form of the receptor that is produced by a conformational change ("flip") that is separate from, and precedes, channel opening. Both the "interaction" scheme and the flip scheme describe our data well, but the latter has fewer free parameters and above all it offers a mechanism for the affinity increase. Distinguishing between the two mechanisms will be important for our understanding of the structural dynamics of activation in the nicotinic superfamily and is important for our understanding of mutations in these receptors

Outcome Measurement and Functional Prognosis in early Multiple Sclerosis

Bouter, L.M. [Promotor]Lankhorst, G.J. [Promotor]Polman, C.H. [Promotor]Beckerman, H. [Copromotor

Heterotic free fermionic and symmetric toroidal orbifold models

Free fermionic models and symmetric heterotic toroidal orbifolds both constitute exact backgrounds that can be used effectively for phenomenological explorations within string theory. Even though it is widely believed that for Z2xZ2 orbifolds the two descriptions should be equivalent, a detailed dictionary between both formulations is still lacking. This paper aims to fill this gap: We give a detailed account of how the input data of both descriptions can be related to each other. In particular, we show that the generalized GSO phases of the free fermionic model correspond to generalized torsion phases used in orbifold model building. We illustrate our translation methods by providing free fermionic realizations for all Z2xZ2 orbifold geometries in six dimensions.Comment: 1+49 pages latex, minor revisions and references adde

Hard thermal loops with a background plasma velocity

I consider the calculation of the two and three-point functions for QED at finite temperature in the presence of a background plasma velocity. The final expressions are consistent with Lorentz invariance, gauge invariance and current conservation, pointing to a straightforward generalization of the hard thermal loop formalism to this physical situation. I also give the resulting expression for the effective action and identify the various terms.Comment: 11 pages, no figure