LIFE SCIENCES

Most biological functions are mediated by conformational changes and specific association of protein molecules. Atomistic simulations are ideal to study the molecular details of such systems. However, often the associated timescales are beyond the maximum simulation times that can be reached even on supercomputers. In this project, researchers developed and tested advanced sampling simulations to accelerate protein domain motions and association of partner molecules. These techniques allow to study domain motions and association of protein molecules on currently accessible time scales. They were successfully applied to study the Hsp90 chaperone protein and to several protein-protein and protein-peptide systems of biological importance.

The conformations of ubiquitin chains are crucial for the so-called ubiquitin code, i.e. the selective signaling of ubiquitylated proteins for different fates in the eukaryotic cellular system. Extensive molecular dynamics simulations at two resolution levels were carried out for ubiquitin di-, tri- and tetramers of all possible linkage types. Analyzing the resulting, exceedingly large high-dimensional data sets was made possible by combining highly efficient neural network based dimensionality reduction with density based clustering and a metric to compare conformational spaces. The so obtained conformational characteristics of ubiquitin chains could be correlated with linkage-type and chain-length dependent experimental observations.

GPCRs sit in the cell membrane and transmit signals from the outside of the cell to its interior. Currently, drugs targeting these receptors only work by mimicking ligands, i.e. they activate or inhibit the receptors by changing their conformation. If the GPCR adopts an active conformation, it can bind proteins on the intracellular side of the cellular membrane, which then transmit the signal inside the cell. In this study, we investigated how a protein that stops the GPCR from signaling, interacts with a prototypical GPCR. We discovered that specific lipids can modify how signals are transmitted by modifying the way of interaction between the GPCR and arrestin. In the future this could enable the discovery of a new kind of drugs for GPCRs.

Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the folding and stabilization of a wide variety of client proteins in eukaryotes. Many of these processes are associated with cancer and other diseases, making Hsp90 an attractive drug target. Hsp90 is a highly flexible protein that can adopt a wide range of distinct conformational states, which in turn are tightly coupled to the enzyme’s ATPase activity. In this project, atomistic molecular dynamics simulations, free energy calculations, and hybrid quantum mechanics/classical mechanics simulations were performed on both monomeric and full-length dimeric Hsp90 models to probe how long-range effects in the global Hsp90 structure regulate ATP-binding and hydrolysis.

Complex I is the largest and most intricate respiratory enzyme, which couples the free energy released from quinone reduction to transfer protons across a biological membrane. Recent X-ray structures of bacterial and eukaryotic complex I have advanced our understanding of the enzyme’s function, but the mechanism of its long-range energy conversion remains unsolved. Here, we use atomistic molecular dynamics simulations and free energy calculations to study how the protonation state, hydration dynamics, and conformational dynamics of complex I regulate its proton pumping activity. Our simulations mimic transient states in the enzyme’s pumping cycle to draw a molecular picture of the protonation signals along the membrane domain of complex I.

The approximately 800 G-protein coupled receptors (GPCRs) in the human genome regulate communication across cell walls. They are targeted by approximately 40% of all marketed drugs. The project uses molecular-dynamics (MD) simulations to investigate ligand binding and receptor activation processes in GPCRs. An activation index for Class A GPCRs has been developed from a series of µsec molecular-dynamics simulations and tested for 275 published X-ray structures.  Binding of the α-domain of G proteins to GPCRs has also been characterized in detail. Metadynamics simulations in conjunction with unbiased MD simulations demonstrated the effect of mutations on the GPCR-ligand interaction in the histamine H₁ receptor.

Intramembrane proteases control the activity of membrane proteins and occur in all organisms. A prime example is g-secretase, cleaving the amyloid precursor protein, whose misprocessing is related to onset and progression of Alzheimer's disease. Since a protease's biological function depends on its substrate spectrum, it is essential to study the repertoire of natural substrates as well as determinants and mechanisms of substrate recognition and cleavage—which is the aim of this collaborative research project. Conformational flexibility of substrate and enzyme plays an essential role for recognition, complex formation and subsequent relaxation steps leading to cleavage and product release.

Diabetes reaches epidemic proportions with a major and growing economic impact on the society. An effective treatment requires atomic-level understanding of how insulin acts on cells. Using molecular dynamics simulations, an international team of researchers studied the process of insulin binding to its receptor and the resulting structural changes at atomic scale with cryogenic election microscopy and atomistic MD simulation. The results of these studies were recently published in the Journal of Cell Biology.

ATP synthase is an enzyme found in organisms ranging from primitive bacteria to some of the most complex lifeforms, such as humans. Its energetic efficiency is unrivalled, but not well understood. Researchers of Gdansk University of Technology have been using HPC to study this remarkable enzyme at a level of detail never seen before.

Computational mechanistic modelling using systems of ordinary differential equations (ODE) has become an integral tool in systems biology. Parameters of such models are often not known in advance and need to be inferred from experimental data, which is computationally very expensive. The SuperMUC supercomputer enabled researchers from the Helmholtz Zentrum Munich to evaluate state-of-the-art algorithms and to develop novel, more efficient algorithms for parameter estimation from large datasets and relative measurements.

Designing new enzymes is a grand challenge for modern biochemistry, and there are few examples for artificial enzymes with significant catalytic rate accelerations. We have developed a new method for computational enzyme design where we mimic evolution in nature and randomly mutate amino acids using a Metropolis Monte Carlo (MC) procedure. The aim of the method is to identify substitutions that increase the catalytic activity of enzymes. We probe the catalytic activity by quantum mechanics/classical mechanics (QM/MM) calculations, which are important for accurately modeling chemical reactions.

Respiratory complex I is the largest and most intricate enzyme of the respiratory chain and responsible for converting energy from the reduction of quinone into an electrochemical proton gradient. The aim of the project is to identify key steps in the catalytic process during enzyme turnover, and to understand the mechanism of the long-range electrostatic coupling between sites located up to 200 Å apart. Large-scale Molecular Dynamics simulations of the entire enzyme enabled the exploration of different aspects of its function. These results provide both information on the redox coupling in complex I and how natural enzymes couple distal sites by propagation of electrostatic interactions.

The generation and assembly of Aβ peptides into pathological aggregates is associated with neurodegenerative diseases including Alzheimer’s disease. Goal of this project was to better understand the dynamics of γ-secretase a key enzyme for the formation of Aβ peptides using large scale Molecular Dynamics simulations and how it associates with substrate molecules. Using the HPC system SuperMUC it was possible to characterize local and global motions of γ-secretase in atomic detail and how it is related to function. In addition, large scale simulations were employed to investigate the amyloid propagation mechanism at the tip of an already formed amyloid fragment. The kinetics and thermodynamics of the process were analyzed and compared to…

Ion channels play a fundamental role in maintaining vital electrochemical gradients across the cell membrane and in enabling electrical signaling across cells. Key characteristics of ion channel function that can be experimentally quantified include ion permeation rates and selectivities. In this project, the functional mechanism of a very important class of ion channels is investigated with the help of molecular dynamics simulations. The computer simulations exhibit a wide range of GLIC states from completely closed to wide open, with conductance and selectivity for the open state in agreement with experimental values. The scientists are now beginning to investigate the intricate opening/closing mechanism in detail to ultimately explain it…

Rapid and accurate calculation of binding free energies is of major concern in drug discovery and personalized medicine. A pan-European research team leveraged the computing power of LRZ’s SuperMUC system to predict the strength of macromolecular binding free energies of ligands to proteins. An in-house developed, highly automated, molecular-simulation-based free energy calculation workflow tool assisted the team in achieving optimal efficiency in its modelling and calculations, resulting in rapid, reliable, accurate and precise predictions of binding free energies.

HIV is one of the most significant global public health threats. The virus evolves rapidly, and multi-drug resistant strains have already emerged. The drugs approved to date target only four HIV proteins. While two novel drug targets, Rev and the capsid protein (CA), have been identified, so far none have reached clinical trials. Scientists leverage the computing power of HPC system SuperMUC to simulate detailed and accurate models of the protein-protein interactions of these targets with the aim to facilitate the design of more effective drugs.

Integral membrane proteins exhibit conformational flexibility at different structural levels and time scales. Our work focusses on the biophysical basis of the interdependence of transmembrane helix dynamics, helix-helix recognition, and helix-lipid interactions. In this context, we try to understand the impacts of these phenomena on biological processes, such as membrane fusion, lipid translocation, and intramembrane proteolysis. Our approach closely connects experimental work and established computational analysis in order to interpret and guide the experiments and to validate the simulations.

Leveraging the computing power of HPC system SuperMUC, researchers of the Technische Universität München investigated the free energy landscape for large-scale conformational changes coupled to the association of biomolecules. It allowed understanding the mechanism of substrate and inhibitor binding to the adenylate kinase (ADK) enzyme and helped to characterize the thermodynamics and kinetics of the propagation of Alzheimer Alzheimer Aβ_9-40 amyloid fibrils.

While some proteins of a biological cell are bound to cellular structures others diffuse freely. Especially in a crowded cellular environment, proteins constantly bump into other proteins which sometimes leads to biologically meaningful contact of the two proteins–the binding partners may either remain bound or a chemical reaction may take place. Performing atomistic molecular dynamics simulations on SuperMUC, bioinformaticists try to unravel the biophysical principles underlying such “specific” biomolecular interactions.

Scientists leverage high performance computing technologies to identify the morphological characteristics of intracranial aneurysms that result in high frequency fluctuations, and assess the role of these fluctuations in aneurysmal wall degradation and consequently aneurysm rupture. Using SuperMUC they performed simulations with up to one billion elements, which allowed the simulation of flow at spatial and temporal resolutions of 8µm and 1µs, while resolving the smallest structures that can develop in a turbulent flow.

Leveraging the computing capacities of HPC system SuperMUC, computer scientists conducted large-scale evolutionary analysis projects of birds and insects. Input datasets comprising 50-100 transcriptomes (the entirety of all RNA molecules in a genome) or genomes that represent the species under study requires supercomputers. Just computing the plausibility of a single out of trillions and trillions of possible evolutionary scenarios requires several terabytes of main memory, and billions of arithmetic operations are required.

Ligand-gated ion channels (LGIC) play a central role in intercellular communication in the central and peripheral nervous systems as well as in non neuronal cells. Understanding their function at an atomic level of detail will be beneficial for the development of drug therapies against a range of diseases including Alzheimer's disease, schizophrenia, pain, and depression. By capitalizing on the increasing availability of high-resolution structures of both pentameric and trimeric LGICs we aim at elucidating the molecular mechanism underlying activation/deactivation by atomistic Molecular Dynamics (MD) simulations, which is essential to rationalize the design of potent allosteric modulators.

Protein kinases are the key enzymes that control most cellular activities. A kinase that fails to work properly can therefore cause severe damage to the organism, causing diverse diseases including cancer. It is therefore highly desirable to develop drugs that modulate the activity of specific protein kinases. Using the supercomputing infrastructure of the Leibniz Supercomputing Centre in Garching near Munich, a team of scientists set out to shed light on the effect of the SH2 domain on the intrinsic motions of the catalytic domain.

Using Petascale system SuperMUC of the Leibniz Supercomputing Centre in Garching/Munich, scientists conducted simulations of mutated proteins to quantify and understand the mechanism of the change in population of binding compatible versus non-compatible states. This resulted in a predicted change in binding affinity which is a property that can be validated experimentally.

The structural characterization of disordered proteins is an inherently under-determined problem: a small number of restraints are insufficient to uniquely define the conformations of a system with thousands of degrees of freedom. Molecular simulations, with their empirical force fields, can offer the additional information required to obtain conformational ensembles for disordered states of proteins. However, these simulations must contend with a massive sampling problem, which was successfully achieved by a team of scientists of the Max Planck Institute for Biophysical Chemistry in Göttingen using HPC system SuperMUC.

A significant part of modern mortality is contributed by strokes, caused by the rupture of intracranial aneurysms (IA). Nearly 4-5% of the world population is reported to be suffering from IA. The deployment of a flow diverter stent in the parent artery of an aneurysm is a novel and minimally invasive treatment procedure, which can cause complete obliteration of the aneurysm by thrombosis.

The process of protein-protein complex formation is of fundamental importance for a better understanding of a variety of biological processes. In a cellular environment the high concentration of surrounding proteins can influence the association process between proteins. Aim of the research project was to simulate the formation of specific and non-specific protein-protein complexes and to investigate the effect of additional protein molecules (crowding) on complex formation in atomic detail. 

The mechanisms of interaction between solid excipients and drugs are based on surface chemistry related phenomena. Consequently, understanding the physico-chemical features of surfaces is a fundamental step to describe and predict the strength of these interactions. The results of this analysis can shed light on how the nature of the excipient can affect the properties of a drug formulation. Among silica-based mesoporous materials, MCM-41 (Mobil Composition of Matter) is one of the most studied. In 2001 it was first proposed as a drug delivery system, with ibuprofen as a model drug. 

Detailed knowledge about the structural and dynamical properties of biomolecules is essential for Life Sciences, from fundamental research to medical drug design. Molecular dynamics simulations are a valuable tool that complement experimental results and help to understand them. Molecular mechanics enable simulations of large systems, such as a protein in solution with several ten thousand atoms, up to a microsecond time scale. However, such simulations are by far not accurate enough for tasks like calculating infrared spectra. In contrast, high-level quantum mechanical methods like density functional theory provide the required accuracy, but are computationally limited to much smaller length and time scales.

Using high-performance computer simulations and novel ways of analysing forces within proteins, a team of scientists of the Molecular Biomechanics Group at the Heidelberg Institute of Theoretical Studies (HITS) under leadership of Dr. Frauke Gräter analysed how the heat shock protein Hsp90, a helper protein vital to any cell in any organism, is switched by the binding of a small molecule.

Using HPC simulations, scientists are doing research on novel single-molecule manipulation techniques in biophysics and bio-nanotechnology to analyse the dynamics of the DNA macromolecule exposed to hydrodynamic flow and complex DNA-liquid interactions by numerical simulations.

Mechanical ventilation for patients suffering from lung diseases can lead to severe complications. Computer simulations contribute to gaining new insights into so called ventilation-induced lung injuries.

A team of scientists from Technische Universität München conduct molecular dynamics simulations on GCS HPC systems to probe the interactions of transmembrane domains, their structural dynamics, and their impact on the surrounding membrane.