22 research outputs found
Time-lagged autoencoders: Deep learning of slow collective variables for molecular kinetics
Inspired by the success of deep learning techniques in the physical and
chemical sciences, we apply a modification of an autoencoder type deep neural
network to the task of dimension reduction of molecular dynamics data. We can
show that our time-lagged autoencoder reliably finds low-dimensional embeddings
for high-dimensional feature spaces which capture the slow dynamics of the
underlying stochastic processes - beyond the capabilities of linear dimension
reduction techniques
Markov State Models from short non-Equilibrium Simulations - Analysis and Correction of Estimation Bias
Many state-of-the-art methods for the thermodynamic and kinetic characterization of large and complex biomolecular systems by simulation rely on ensemble approaches, where data from large numbers of relatively short trajectories are integrated. In this context, Markov state models (MSMs) are extremely popular because they can be used to compute stationary quantities and long-time kinetics from ensembles of short simulations, provided that these short simulations are in “local equilibrium” within the MSM states. However, over the last 15 years since the inception of MSMs, it has been controversially discussed and not yet been answered how deviations from local equilibrium can be detected, whether these deviations induce a practical bias in MSM estimation, and how to correct for them. In this paper, we address these issues: We systematically analyze the estimation of MSMs from short non-equilibrium simulations, and we provide an expression for the error between unbiased transition probabilities and the expected estimate from many short simulations. We show that the unbiased MSM estimate can be obtained even from relatively short non-equilibrium simulations in the limit of long lag times and good discretization. Further, we exploit observable operator model (OOM) theory to derive an unbiased estimator for the MSM transition matrix that corrects for the effect of starting out of equilibrium, even when short lag times are used. Finally, we show how the OOM framework can be used to estimate the exact eigenvalues or relaxation time scales of the system without estimating an MSM transition matrix, which allows us to practically assess the discretization quality of the MSM. Applications to model systems and molecular dynamics simulation data of alanine dipeptide are included for illustration. The improved MSM estimator is implemented in PyEMMA of version 2.3
a swarm intelligence-based optimizer for molecular geometry
We present a stochastic, swarm intelligence-based optimization algorithm for
the prediction of global minima on potential energy surfaces of molecular
clusterstructures. Our optimization approach is a modification of the
artificial bee colony (ABC) algorithm which is inspired by the foraging
behavior of honey bees. We apply our modified ABC algorithm to the problem of
global geometryoptimization of molecular clusterstructures and show its
performance for clusters with 2–57 particles and different interatomic
interaction potentials
HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells
Objective Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. Design Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. Results NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. Conclusion Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis
Protonenleitung mittels großskaliger atomistischer Simulationen
The simulation of large and complex molecular systems is a very challenging
task, especially under realistic conditions. A case in point is the phenomenon
of proton conduction in fuel cell membranes, which is the main topic addressed
in this work. The computational modeling of this transport phenomenon is still
far from being a routine problem, despite the fast development of
computational infrastructure. The general phenomenon of ion conduction in
condensed matter consists of a multitude of facets. In this thesis, I address
several aspects of this phenomenon for the specific case of the proton
transport in hexakis(p-phosphonatophenyl)benzene, an organic compound that is
a promising material for high temperature fuel cell membranes. I have
performed large-scale atomistic simulations with electronic structure methods
to elucidate the proton conduction mechanism in this material. The simulations
show that this compound self-organizes in supramolecular columnar stacks with
a tight intermolecular/interstack hydrogen bond network, which is in good
agreement with experimental results. In particular, the simulations show the
direct motion of individual protons in the dynamically fluctuating hydrogen
bond network. Interestingly, the hydrogen bond network forms quasi-one-
dimensional channels in the interstice of adjacent supramolecular stacks and
parallel to the columnar axis. The observed motion of the protons shows that
the diffusion is most pronounced in these channels. The applied part of my
work is a case in point for large-scale simulations under realistic
conditions. Such large-scale simulations, however, also require large-scale
methods. The second and more theoretical part of my thesis addresses the
development of such large-scale methods, specifically, for quantum-classical
calculations. Hybrid quantum-classical (QM/MM) calculations combine the
ability of classical methods to treat large molecular systems with the
advantage of quantum methods to model chemical processes within smaller
fragments of the system. I have developed an approach to increase the accuracy
of QM/MM calculations with a particular emphasis on spectroscopic parameters;
this approach aims at extending the applicability of first-principles
spectroscopy calculations to large-scale systems. The second development
subproject targets molecular structure prediction by means of numerical
calculations. This is one of the evergreen problems in chemical physics but
also one of the most difficult challenges. Specifically the determination of
the global minimum structure is a field of intense research. For this aim, I
have developed a stochastic, swarm intelligence-based optimization algorithm
to the problem of global geometry optimization.Die Simulation von großskaligen und komplexen molekularen Systemen ist eine
große Herausforderung, insbesondere, wenn die Simulation unter realistischen
Bedingungen durchgeführt werden soll. Das zentrale Thema dieser Dissertation
ist die Protonenleitung in Brennstoffzellmembranen und ein typisches Beispiel
für solch eine Simulation. Die numerische Modellierung dieses
Transportphänomens ist allerdings ausgesprochen aufwendig, trotz der rasanten
Leistungsfähigkeitssteigerung modernen Computer. Das allgemeine Phänomen der
Ionenleitung in kondensierter Materie hat viele Facetten. Im Rahmen dieser
Dissertation untersuche ich einige dieser Aspekte für den speziellen Fall von
Protonenleitung in Hexakis(p-Phosphonatophenyl)benzol, einer organischen
Verbindung mit großem Potential für die Anwendung in Brennstoffzellmembranen.
In meiner Arbeit habe ich großskalige, atomistische Simulationen auf Basis der
Elektronenstrukturtheorie durchgeführt, um den Leitungsmechanismus in diesem
Material zu untersuchen. Die Simulationen zeigen, dass sich dieses Material
selbst in supramolekularen Stapeln anordnet und ein dichtes intermolekulares
Netzwerk aus Wasserstoffbrücken ausbildet; diese Resultate stimmen gut mit
experimentellen Beobachtungen überein. Inbesondere erlauben die Simulationen,
die Bewegung der einzelnen Protonen im dynamisch fluktuierenden
Wasserstoffbrückennetzwerk direkt zu beobachten. Interessanterweise bildet das
Wasserstoffbrückennetzwerk quasi-eindimensionale Kanäle im Zwischenraum
benachbarter Stapel, die parallel zu den Stapelachsen angeordnet sind. Die
Analyse der direkten Protonenbewegung zeigt, dass die Protonendiffusion
innerhalb dieser Kanäle besonders ausgeprägt ist. Dieses anwendungsorientierte
Projekt meiner Arbeit ist ein typisches Beispiel für großskalige Simulationen
unter realistischen Umgebungsbedingungen. Solch großskalige Simulationen
stützen sich allerdings auch auf großskalige Simulationemethoden, deren
Entwicklung den zweiten, methodisch orientierten Teil dieser Dissertation
ausmachen: Hybrid-quantenmechanisch-klassische (QM/MM) Simulationsmethoden
erlauben es, die Vorteile klassischer und quantenmechanischer Methoden zu
kombinieren. Dabei wird ein großskaliges System klassisch modelliert und nur
ein Fragment auf Basis der Elektronenstrukturtheorie behandelt. Hierfür habe
ich ein Verfahren zur Verbesserung der Genauigkeit dieser Methode entwickelt,
die insbesondere die Qualität von spektroskopischen Berechnungen erhöht.
Dieses Teilprojekt hat zum Ziel, die Anwendbarkeit von
Spektroskopieberechnungen auf großskalige Systeme auzudehnen. Das zweite
Teilprojekt betrifft die Vorhersage molekularer Struktur mittels numerischer
Rechnungen. Dies stellt eine der zentralen Fragestellungen im Feld der
chemischen Physik dar und ist gleichzeitig eine der größten Herausforderungen.
Insbesondere die Bestimmung des globalen Minimums ist ein vielbeachtetes Feld.
Für dieses Problem habe ich einen stochastischen Algorithmus aus dem Feld der
Schwarmintelligenz adaptiert und daraus einen globalen Optimierer für
molekulare Geometrien entwickelt
Moving Program Objects to Scratch-Pad Memory for Energy Reduction £
This paper presents a new approach for improving energy consumption of compiler generated software by using on-chip Scratch-Pad RAM more efficiently. This memory allocation technique moves program parts (functions or basic blocks and global data objects) into the limited Scratch-Pad RAM. Experimental results show that this technique saves up to 80 % of the total energy consumption depending on the application, the system architecture and the size of the Scratch-Pad RAM
A Coupled Molecular Dynamics/Kinetic Monte Carlo Approach for Protonation Dynamics in Extended Systems
We propose a multiscale
simulation scheme that combines first-principles
Molecular Dynamics (MD) and kinetic Monte Carlo (kMC) simulations
to describe ion transport processes. On the one hand, the molecular
dynamics trajectory provides an accurate atomistic structure and its
temporal evolution, and on the other hand, the Monte Carlo part models
the long-time motion of the acidic protons. Our hybrid approach defines
a coupling scheme between the MD and kMC simulations that allows the
kMC topology to adapt continuously to the propagating atomistic microstructure
of the system. On the example of a fuel cell membrane material, we
validate our model by comparing its results with those of the pure
MD simulation. We show that the hybrid scheme with an evolving topology
results in a better description of proton diffusion than a conventional
approach with a static kMC transfer rate matrix. Furthermore, we show
that our approach can incorporate additional dynamical features such
as the coupling of the rotation of a side group in the molecular building
blocks. In the present implementation, we focus on ion conduction,
but it is straightforward to generalize our approach to other transport
phenomena such as electronic conduction or spin diffusion
Water-Free Proton Conduction in Hexakis(<i>p</i>‑Phosphonatophenyl)benzene Nanochannels
We
elucidate the proton conduction mechanism in self-assembling stacks
of phosphonic-acid-functionalized molecules (hexakis(<i>p</i>-phosphonatophenyl)benzene) at different temperatures (400–600
K) and at zero humidity conditions. We employ first-principles molecular
dynamics simulations in combination with large-scale force-field simulations,
forming a specific arrangement of the molecules in the columnar stacks.
This arrangement leaves space for quasi-one-dimensional hydrogen bond
nanowires along which protons are transported. We observe spontaneous
autodissociation of the phosphonic acid groups, leading to proton
displacements of up to 10 Å along the nanowires. Our simulations
show that there is a fast (200 fs) and a slow (3–12 ps) component
in the dynamics of the hydrogen bond network, corresponding to orientation
fluctuations of the hydrogen bonds and persistent long-range proton
transport, respectively. Our results support the hypothesis that significant
proton conduction is possible in this compound at fully dehydrated
conditions and at high temperatures. In such circumstances, the material
may outperform the common Nafion polymer as membrane materials for
proton exchange fuel cells