Jens Krüger

The MoSGrid Science Gateway - A Complete Solution for Molecular Simulations

The MoSGrid portal offers an approach to carry out high-quality molecular simulations on distributed compute infrastructures to scientists with all kinds of background and experience levels. A user-friendly Web interface guarantees the ease-of-use of modern chemical simulation applications well established in the field. The usage of well-defined workflows annotated with metadata largely improves the reproducibility of simulations in the sense of good lab practice. The MoSGrid science gateway supports applications in the domains quantum chemistry (QC), molecular dynamics (MD), and docking. This paper presents the open-source MoSGrid architecture as well as lessons learned from its design.

Regulation of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) Channel Activity by cCMP

Background: HCN channels are dually gated by membrane hyperpolarization and binding of cAMP. Results: We identify cCMP as a novel regulator of heterologously expressed and native HCN channels. Conclusion: HCN channels are cellular receptors for cCMP. Significance: Modulatory effects of cCMP must be considered when studying physiological effects involving HCN channels. Activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is facilitated in vivo by direct binding of the second messenger cAMP. This process plays a fundamental role in the fine-tuning of HCN channel activity and is critical for the modulation of cardiac and neuronal rhythmicity. Here, we identify the pyrimidine cyclic nucleotide cCMP as another regulator of HCN channels. We demonstrate that cCMP shifts the activation curves of two members of the HCN channel family, HCN2 and HCN4, to more depolarized voltages. Moreover, cCMP speeds up activation and slows down deactivation kinetics of these channels. The two other members of the HCN channel family, HCN1 and HCN3, are not sensitive to cCMP. The modulatory effect of cCMP is reversible and requires the presence of a functional cyclic nucleotide-binding domain. We determined an EC50 value of ∼30 μm for cCMP compared with 1 μm for cAMP. Notably, cCMP is a partial agonist of HCN channels, displaying an efficacy of ∼0.6. cCMP increases the frequency of pacemaker potentials from isolated sinoatrial pacemaker cells in the presence of endogenous cAMP concentrations. Electrophysiological recordings indicated that this increase is caused by a depolarizing shift in the activation curve of the native HCN current, which in turn leads to an enhancement of the slope of the diastolic depolarization of sinoatrial node cells. In conclusion, our findings establish cCMP as a gating regulator of HCN channels and indicate that this cyclic nucleotide has to be considered in HCN channel-regulated processes.

Assembly of Viral Membrane Proteins.

The generation of computational models is an alternative route to obtain reliable structures for the oligomeric state of membrane proteins. A strategy has been developed to search the conformational space of all possible assemblies in a reasonable time, taking symmetry considerations into account. The methodology tested on M2 from influenza A, shows an excellent agreement with established structures. For Vpu from HIV-1 a series of conformational distinct structures are proposed. For the first time a structural model for a fully assembled transmembrane part of 3a from SARS-CoV is proposed.

A Single Sign-On Infrastructure for Science Gateways on a Use Case for Structural Bioinformatics

Structural bioinformatics applies computational methods to analyze and model three-dimensional molecular structures. There is a huge number of applications available to work with structural data on large scale. Using these tools on distributed computing infrastructures (DCIs), however, is often complicated due to a lack of suitable interfaces. The MoSGrid (Molecular Simulation Grid) science gateway provides an intuitive user interface to several widely-used applications for structural bioinformatics, molecular modeling, and quantum chemistry. It ensures the confidentiality, integrity, and availability of data via a granular security concept, which covers all layers of the infrastructure. The security concept applies SAML (Security Assertion Markup Language) and allows trust delegation from the user interface layer across the high-level middleware layer and the Grid middleware layer down to the HPC facilities. SAML assertions had to be integrated into the MoSGrid infrastructure in several places: the workflow-enabled Grid portal WS-PGRADE (Web Services Parallel Grid Runtime and Developer Environment), the gUSE (Grid User Support Environment) DCI services, and the cloud file system XtreemFS. The presented security infrastructure allows a single sign-on process to all involved DCI components and, therefore, lowers the hurdle for users to utilize large HPC infrastructures for structural bioinformatics.

Exploring the conformational space of Vpu from HIV-1: a versatile adaptable protein.

The dynamic behavior of monomeric Vpu1‐32 from HIV‐1 in different lipid environments has been studied. The peptide shows highly flexible behavior during the simulations and easily adapts to changing lipid environments as it experiences when travelling through the Golgi apparatus. Protein–lipid interactions do not show any significant correlation towards lipid type or thickness based on multiple 10 ns simulations. The averaged structure of a series of 16 independent simulations suggest kink around Ser‐24, which compensates the polarity of its side chain by forming hydrogen bonds with the carbonyl backbone of adjacent amino acids towards the N‐terminus.

CELLmicrocosmos 2.2 MembraneEditor: A Modular Interactive Shape-Based Software Approach To Solve Heterogeneous Membrane Packing Problems

New perspectives have been developed to understand the processes of modeling heterogeneous membranes. These are crucial steps prior to applying advanced techniques like molecular dynamic simulations of whole membrane systems. Lipid, protein, and membrane packing problems are addressed based on biochemical properties in combination with computational optimization techniques. The CELLmicrocosmos 2.2 MembraneEditor (CmME) is introduced as an appropriate framework to handle such problems by offering diverse algorithmic approaches. Its algorithm plug-in-interface enables modelers to generate problem-specific algorithms. Good solutions concerning runtime and lipid density are realized by focusing on the outer shapes of the PDB-based molecules. Application cases are presented like the publication-based modeling of inner and outer mitochondrial membrane-fragments, semiautomatic incorporation of proteins, and the assembly of rafts. Concerning geometrical aspects of the lipids, the achieved results are consistent with experimental observations related to lipid densities and distributions. Finally, two membranes simulated with GROMACS are analyzed and compared: the first is generated with conventional scripting techniques, the second with the CmME Distributor algorithm. The examples prove that CmME is a valuable and versatile tool for a broad set of applications in analysis and visualization of biomembranes.

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR domain oligomerization

Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear factor κB signaling. We found that mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines, mimicking the effect of dimerized TIR domains. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous wild-type MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization.

Structural Stability of V-Amylose Helices in Water-DMSO Mixtures Analyzed by Molecular Dynamics.

Computational techniques have been employed to fundamentally understand the behavior of helically structured amylose in water/DMSO mixtures. Using a computationally generated amylose helix of 55 glucose residues, we have investigated the time-dependent behavior of intra- and intermolecular hydrogen bonds, particularly between O2 and O3 of adjacent glucose molecules and between O6 and neighboring O2 and O3 groups. The helix character was defined by the total number of residually existing hydrogen bonds. Our results parallel the experimental finding that increasing the percentage of DMSO results in increasing helical stability. It can be shown that O6-O2/O3 hydrogen bonds are preferentially lost when the helix starts to unfold to a finally resulting random coil structure. While water is small enough to interact with every hydroxyl group at the helix surface and finally penetrate the helix coil, DMSO can initially only form single hydrogen bonds to part of the OH groups of the amylose molecule, thereby allowing a longer conservation of intramolecular hydrogen bonds that are necessary to maintain the helix. However, given a long enough time for interaction, the helical structure of amylose is lost in water as well as in DMSO, yielding a random orientation of the glucose strand.

Enforcing SLAs in Scientific Clouds

Software as a Service (SaaS) providers enable the on-demand use of software, which is an intriguing concept for business and scientific applications. Typically, service level agreements (SLAs) are specified between the provider and the user, defining the required quality of service (QoS). Today SLA aware solutions only exist for business applications. We present a general SaaS architecture for scientific software that offers an easy-to-use web interface. Scientists define their problem description, the QoS requirements and can access the results through this portal. Our algorithms autonomously test the feasibility of the SLA and, if accepted, guarantee its fulfillment. This approach is independent of the underlying cloud infrastructure and successfully deals with performance fluctuations of cloud instances. Experiments are done with a scientific application in private and public clouds and we also present the implementation of a high-performance computing (HPC) cloud dedicated for scientific applications.

Viral channel-forming proteins.

Abstract Channel-forming proteins are found in a number of viral genomes. In some cases, their role in the viral life cycle is well understood, in some cases it needs still to be elucidated. A common theme is that their mode of action involves a change of electrochemical or proton gradient across the lipid membrane which modulates the viral or cellular activity. Blocking these proteins can be a suitable therapeutic strategy as for some viruses this may be “lethal.” Besides the many biological relevant questions still to be answered, there are also many open questions concerning the biophysical side as well as structural information and the mechanism of function on a molecular level. The immanent biophysical issues are addressed and the work in the field is summarized.