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A life stilled too early.

On May 5th 2008 Ángel Ramírez Ortiz died of cancer in Madrid at the age of 41. A former fellow of the European Molecular Biology Laboratory (EMBL), and until his death leader of the Bioinformatics Group at the Centre for Molecular Biology "Severo Ochoa" (CBMSO), he was considered worldwide as a very prominent figure in structural bioinformatics, a field of science in which biology, computer science, and information technology merge to form a single discipline. During his early terminated life Ángel never stopped to develop and apply new methodologies in this area in the hope that they would be useful for the rational design of new drugs that could eventually become medicines.

After completing his Pharmacy degree at Complutense University in Madrid, Ángel joined the incipient research group of Federico Gago at the University of Alcalá, where he was early recognized to be clearly above average and highly motivated. Ángel was initially involved in a project financed mostly by Menarini Pharmaceuticals, aimed at the rationalization of the biochemical activity of a number of phospholipase A2 (PLA2) enzymes from different sources and, ultimately, at the design of novel inhibitors of human synovial fluid PLA2 tagged as anti-inflammatory agents. His continuous wish to learn led him to the University of Groningen, The Netherlands, where he spent several months in Prof. Herman Berendsen's laboratory. This stay fostered his interest into the basic physicochemical principles that govern not only ligand binding but also protein folding, a difficult subject that was a "siren song" to his ears and a permanent challenge to his undisputed talent. The PLA2 project proved to be extremely fruitful and there is little doubt that Ángel made important contributions to the understanding of this class of enzymes and also to the emerging subject of cation-pi interactions. Among the corollaries of this work were the development of a method (the so-called COMBINE analysis) for the elucidation of complex three-dimensional structure-activity relationships, in collaboration with Dr. Rebecca Wade at the EMBL in Heidelberg, and the successful design of a synthetic receptor for phosphatidylcholine, in collaboration with Prof. Javier de Mendoza at Autóonoma University in Madrid. In recent years, COMBINE has been shown to perform better than previous methods and has become a well-established and powerful tool in the field of structure-based ligand design.

In addition to this work in biochemical pharmacology, Ángel always found time to devote his mind and a large part of his research efforts to one of his preferred topics: the prediction of protein structure. He was always enthusiastic about this and came up with lots of ideas, which he began to elaborate in the stimulating environment of the EMBL in close contact with Luis Serrano and other researchers. By this time his great competence, superbly organized mind and his enormous working capacity were moulding the natural group leader he was called to be, with strong and well-grounded scientific convictions.

Upon completion of his Ph. D., Ángel left for the United States to join Prof. Jeffrey Skolnick's group at the Department of Molecular Biology at the Scripps Research Institute, where he significantly contributed to the development of MONSSTER, at the time one of the most successful Monte Carlo algorithms for predicting protein structure in the absence of a template, as assessed in the Critical Assessment of Techniques for Protein Structure Prediction (CASP), a contest for which he would soon be acting as an advisor. A few years later, he developed, in collaboration with Bin Qian and David Baker, an original and imaginative framework for assisting homology-based modelling of protein structures making use of both empirical knowledge of protein structure evolution and equilibrium dynamics. His next move was to the Mount Sinai School of Medicine in New York, where he established his own group and expanded his range of interests to the emergent field of genomics. It was during this period that he developed MAMMOTH, a program that is now consolidated as one of the references in the field of protein structure alignment. Besides being fast and reliable, MAMMOTH has a rigorously defined and properly normalized score to assess statistical significance, and the first pair-wise version, which privileged speed at the expense of accuracy, paved the way for the following multiple-alignment version, which became much more accurate and is currently available to the scientific community as a Web server.

Back to Spain, Ángel founded and headed the Bioinformatics Unit at the CBMSO in Madrid, under the auspices of the Spanish Research Council, striving hard not only to create the necessary infrastructure but also to recruit talented students and collaborators from all over the world that could help him materialize his long cherished dreams. In this endeavour he definitely succeeded because he set in motion many ambitious projects. As way of example, he applied the MAMMOTH algorithm to the study of protein structure evolution, unveiling how deeply protein topology constrains the possible evolutionary paths, and efforts are under way to obtain an automatic, objective and consistent classification of protein structures. The other research pillar in his group was the development and optimization of a complete suite of programs to carry out docking and virtual screening experiments aimed at the identification of drug candidates. Those tools are available to perform conformational analysis of small molecules (ALFA), grid-based interaction energy calculations for mapping binding sites in proteins (CGRID), ligand docking (CDOCK), and simplified but accurate computations of solvation and desolvation effects (ISM). All of these programs have been integrated in an user-configurable data management system that currently forms the cornerstone of the "Bioinformatics Integrative Platform for structurE-based Drug Discovery" (BIPEDD) project sponsored by Comunidad de Madrid. This platform agglutinates the expertise of several computational and experimental groups based in Madrid region with a common interest in target recognition, lead identification and characterization of ligand-receptor complexes. A recently published outcome of this collaborative enterprise was the recent discovery of four molecules that act as inhibitors of an enzyme that is largely responsible for the resistance to chemotherapy of some tumour cells, including those from glioblastoma multiforme, the cancer that rather ironically put an end to Ángel's life.

All of those who met Ángel along his career were uniformly impressed by his personality, strong determination, permanent curiosity, contagious enthusiasm, high motivation, and constructive criticisms. He was also unpretentious and always open to listen to different opinions and actively participate in scientific discussions. His courage, sense of responsibility and unwavering will to help others cannot be forgotten and should serve as inspiration to those who are now struggling to keep his human and scientific legacy alive. The dedication and love of his life's companion and wife, Carme Fabrega, especially in the final months, were admirable and another beautiful example worth remembering.

May he rest in peace.

[Download Ángel Ortiz short CV]
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