Parallel multi-objective algorithms for the molecular docking problem

International audienceMolecular docking is an essential tool for drug design. It helps the scientist to rapidly know if two molecules, respectively called ligand and receptor, can be combined together to obtain a stable complex. We propose a new multi-objective model combining an energy term and a surface term to gain such complexes. The aim of our model is to provide complexes with a low energy and low surface. This model has been validated with two multi-objective genetic algorithms on instances from the literature dedicated to the docking benchmarking

Solvent accessible surface area approximations for rapid and accurate protein structure prediction

The burial of hydrophobic amino acids in the protein core is a driving force in protein folding. The extent to which an amino acid interacts with the solvent and the protein core is naturally proportional to the surface area exposed to these environments. However, an accurate calculation of the solvent-accessible surface area (SASA), a geometric measure of this exposure, is numerically demanding as it is not pair-wise decomposable. Furthermore, it depends on a full-atom representation of the molecule. This manuscript introduces a series of four SASA approximations of increasing computational complexity and accuracy as well as knowledge-based environment free energy potentials based on these SASA approximations. Their ability to distinguish correctly from incorrectly folded protein models is assessed to balance speed and accuracy for protein structure prediction. We find the newly developed “Neighbor Vector” algorithm provides the most optimal balance of accurate yet rapid exposure measures

Modelling timing in blood cancers

Dysregulation of biological processes in normal cells can lead to the abnormal growth of tumours. Oncogenesis requires the acquisition of advantageous mutations to expand in a fluctuating environment. Cancer cells gain these genetic and epigenetic alterations at different timing in their development, resulting in the formation of heterogeneous cell populations which interact and compete with each others inside tumours. At later stages, by escaping the immune system and acquiring malignant properties, some cancer cells manage to evade the primary tumour and spread in different organs to form metastases. Hence, tumour development in healthy tissues endure several biological changes whilst progressing and the order between these molecular and cellular events may modify prognosis. This thesis addresses the influence of biological event timing on blood cancer progression and clinical outcomes. It first investigates the therapeutic efficacy of p53 restoration in a lymphoma mouse model. While several therapy schedules are tested, all fail due to resistance emergence. Computational modelling establishes the cell dynamics in these tumours and how to use it to propose alternative treatment strategies. Data availability leads this work to explore the impact of molecular evolution in myeloid malignancies. Notably, one study has found that Myeloproliferative Neoplasms patients with both JAK2 and TET2 mutations have different disease characteristics with distinct mutation order. My analyses identify HOXA9 as a potential prognosis marker and biological switch responsible for patient stratification in these patients and in Acute Myeloid Leukemia. Additionally, a molecular network identifies the hematopoietic regulators involved in the branching evolution of Myeloproliferative Neoplasms. Further investigations of the Acute Myeloid Leukemia data show the possible involvement of APP, a gene associated to Alzheimer disease, in early cell fate commitment in hematopoiesis and in poor survival prognosis in undifferentiated leukemia when lowly expressed. Finally, this thesis examines the regulatory dynamics behind three clusters of Acute Myeloid Leukemia patients with distinct levels of HOXA9 and APP expression. By building a program inferring molecular motifs from biological observations, genes which may interact with HOXA9 and APP are identified.Microsoft Research and the MRC Cancer Unit

Novel Development of a Low-Cost, Micrometer-Scale Tip-Enhanced Raman Spectroscopy System

Modern scientific instruments are significant capital investments for universities. These investments can be outside of the funding capabilities of some smaller universities or departments and can be a significant barrier in the pursuit of scientific breakthroughs. This project aims to provide a template for universities or research groups to upgrade, at a reasonable price, an existing Raman spectroscopy system to a Tip-Enhanced Raman Spectroscopy (TERS) system. This system can serve as a permanent upgrade to an existing system or as a bridge necessary to prove the viability of a research path before significant capital investment in a commercial TERS system. This project explains, in detail, all required components of a TERS system and the rationale of each designed component. The enhancement factor demonstrated using this homebuilt TERS system shows the potential of this system as an alternative to much more expensive commercial systems

Dagstuhl News January - December 2005

"Dagstuhl News" is a publication edited especially for the members of the Foundation "Informatikzentrum Schloss Dagstuhl" to thank them for their support. The News give a summary of the scientific work being done in Dagstuhl. Each Dagstuhl Seminar is presented by a small abstract describing the contents and scientific highlights of the seminar as well as the perspectives or challenges of the research topic

Fault and Defect Tolerant Computer Architectures: Reliable Computing With Unreliable Devices

This research addresses design of a reliable computer from unreliable device technologies. A system architecture is developed for a fault and defect tolerant (FDT) computer. Trade-offs between different techniques are studied and yield and hardware cost models are developed. Fault and defect tolerant designs are created for the processor and the cache memory. Simulation results for the content-addressable memory (CAM)-based cache show 90% yield with device failure probabilities of 3 x 10(-6), three orders of magnitude better than non fault tolerant caches of the same size. The entire processor achieves 70% yield with device failure probabilities exceeding 10(-6). The required hardware redundancy is approximately 15 times that of a non-fault tolerant design. While larger than current FT designs, this architecture allows the use of devices much more likely to fail than silicon CMOS. As part of model development, an improved model is derived for NAND Multiplexing. The model is the first accurate model for small and medium amounts of redundancy. Previous models are extended to account for dependence between the inputs and produce more accurate results

Cutting Edge Nanotechnology

The main purpose of this book is to describe important issues in various types of devices ranging from conventional transistors (opening chapters of the book) to molecular electronic devices whose fabrication and operation is discussed in the last few chapters of the book. As such, this book can serve as a guide for identifications of important areas of research in micro, nano and molecular electronics. We deeply acknowledge valuable contributions that each of the authors made in writing these excellent chapters