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XXI Semana de Biologa Experimental, Universidad Autnoma Metropolitana, Unidad Iztapalapa, 13 de octubre de 2011 1.

La biofisicoqumica o cmo es que la fsica, la qumica y la biologa se comunican para enriquecer el conocimiento cientfico Dr Ral Alva Garca, Biofisicoqumico. Departamento de Ciencias de la Salud, Divisin de Ciencias Biolgicas y de la Salud, Universidad Autnoma Metropolitana, Unidad Iztapalapa 2. Si bien en el siglo XIX, Charles Darwin y Gregor Mendel representaron el parteaguas para una biologa con mayor estructura de pensamiento cientfico, la sntesis qumica abitica de urea por Friedrich Whler no slo representa la muerte de la alquimia y el nacimiento de la qumica con sus dos grandes reas (la inorgnica y la orgnica), sino tambin el evento primordial de interaccin entre la qumica y la biologa mediante el inicio de la comprensin de los aspectos qumicos de la materia biolgica y, por lo tanto, la gestacin de la bioqumica como disciplina 3. Qu es la vida? What is life? : the physical aspect of the living cell ; with, Mindand matter & Autobiographical. Schrdinger, Erwin, 1887-1961. c1992. / QH331 S3.7 This book very elegantly propounded the belief that genes were the key components of living cells and that, to understand what life is, we must know how genes act. When Schrodinger wrote his book (1944) there was general acceptance that genes were special types of protein molecules. But almost at this same time the bacteriologist 0. T. Avery was carrying out experiments at the Rockefeller Institute in New York which showed that hereditary traits could be transmitted from one bacterial cell to another by purified DNA molecules. Nevertheless, a major factor in Francis Crick leaving physics and developing an interest in biology had been the reading in 1946 of What Is Life? by the noted theoretical physicist Erwin Schrodinger 4. Energy is a physics concept that can be defined as the capacity for doing work. For an object of mass m, moving with velocity of magnitude v, this energy can be calculated from the equation Ec= 1/2 mv^2 E=hv E=mc^2 5. Transformacin de energa biolgica puede ser explicada por medio de las leyes de la qumica, ya que son evidentes las transformaciones qumicas de la materia biolgica 6. La Glucolisis es una serie de reacciones qumicas de oxidorreduccin y transferencia qumica directa de fosfatos que producen ATP, que sucede en todos los organismos en la Tierra, desde las bacterias

hasta los mamferos, "acumulando" energa en los enlaces fosfodister C6H12O6 + ADP -> CH3COCOO + H+ + ATP 7. La Fosforilacin Oxidativa es una serie de reacciones bioqumicas de oxidorreduccin de cidos policarboxlicos que indirectamente producen ATP, "acumulando" energa en los enlaces fosfodister. Durante ms de un cuarto de siglo, los laboratorios bioqumicos del mundo trabajaron buscando la forma en que la oxidacin de los cidos tricarboxlicos en el Ciclo de Krebs se acoplaba con la fosforilacin del ADP para sintetizar ATP, proponiendo principalmente dos mecanismos qumicos: un intermediario qumico fosfatado, como el NADP, y cambios conformacionales en la ATPsintetasa, como sucede en las potenas del msculo esqueltico 8. Hace cinco dcadas Peter Mitchell postul un mecanismo qumico y fsico para explicar la tranformacin de energa biolgica, la Hiptesis Quimiosmtica: las membranas biolgicas poseen componentes translocadores de iones que generan un potencial elctrico (fsico) y qumico (de pH) transmembranal; al abatirse cataliza la fosforilacin de ADP a ATP, acumulando energa en los enlaces fosfodister. Este mecanismo fsico y qumico es responsable de la ms eficiente transformacin de energa en todos los seres vivos en la Tierra, desde las bacterias fotosintticas hasta las plantas vasculares y los mamferos "In the exact sciences, cause and effect are no more than events linked in sequence. . . if the processes that we call metabolism and transport represent events in a sequence, not only can metabolism be the cause of transport, but also transport can be the cause of metabolism" Peter Mitchell, Nature, 1961 9. Berton Pressman y Sergio Estrada descubrieron los ionforos peptdicos y carboxlicos que demostraron que la translocacin inica en organelos energticos es electrofortica y define la anisotropa de las membranas biolgicas. Los estudios en mitocondrias, cloroplastos, bacterias quimitrofas y fottrofas, demostraron que el potencial de membrana es la fuerza motriz que impulsa a la sntesis biolgica de ATP y que realiza la translocacin de iones necesaria para el metabolismo 10. En palabras de Efraim Racker, "el problema central de la fosforilacin acoplada a la oxidacin y el transporte de iones [...] haba sido, al fin, resuelto" 11. Lo que fue finalmente reconocido mediante la adjudicacin del Premio Nobel de Qumica a Peter Mitchell en 1978, como la "contribucin a la comprensin de la transferencia de energa biolgica" 12. Biophysical chemistry is a relatively new branch of chemistry that covers a broad spectrum of research activities involving biological systems. The most common feature of the research in this subject is to seek explanation of the various phenomena in biological systems in terms of either the molecules that make up the system or the supra-molecular structure of these systems 13. Biophysical chemists employ various techniques used in physical chemistry to probe the structure of biological systems. These techniques include spectroscopic methods like nuclear magnetic resonance 2

(NMR) and X-ray diffraction 14. For example, the work for which Nobel Prize was awarded in 2009 to three chemists was based on xray diffraction studies of ribosomes. Some of the areas in which biophysical chemists engage themselves are protein structure and the functional structure of cell membranes. For example, enzyme action can be explained in terms of the shape of a pocket in the protein molecule that matches the shape of the substrate molecule or its modification due to binding of a metal ion. Similarly the structure and function of the biomembranes may be understood through the study of model supramolecular structures as liposomes or phospholipid vesicles of different compositions and sizes 15. The oldest reputed institute for biophysical chemistry is Max Planck Institute for Biophysical Chemistry in Gttingen (Karl Friedrich Bonhoeffer Institute) was created in 1971 through the merger of two Max Planck Institutes in Gttingen, the Institute for Physical Chemistry, founded in 1949, and the Institute for Spectroscopy, was one of the first who applied physical-chemical methods in biological research and thus made different disciplines of natural sciences to interact in research, like rapid reaction kinetics, single channel recording techniques and applications 16. Biophysical Chemistry. An international journal devoted to the physics and chemistry of biological phenomena. Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as singlemolecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal. 17. Yale Department of Chemistry Biophysical Chemistry The goal of the biophysical chemist is to provide physical explanations for the ways in which important biological systems function. Techniques needed to reach this goal are drawn from many disciplines including chemistry, physics, and biology. Spectroscopic tools such as NMR spectroscopy are combined with diffraction methods to define molecular structure at an atomic level. Electronic structure of active sites is probed with optical, vibrational, and EPR spectroscopies. The time course of catalyzed processes is followed by time-resolved laser spectroscopy along with traditional kinetic methods. Functional models are tested by altering macromolecular structure using the techniques of molecular biology and organic synthesis. Ultimately, processes and structures may be modeled with computer programs that incorporate our best understanding of the electronic structure of the biomolecular building blocks. 18. Las investigaciones sobre los complejos que forman los acarreadores mviles modelo -como los 3

politeres carboxlicos y los teres corona- con diversas especies inicas, establecieron las bases fsicas y qumicas de la actividad quimiosmtica. Fue posible indicar los aspectos fisicoqumicos de flexibilidad estructural que constituyen y regulan la translocacin inica catalizada. 19. La funcin de las osmoenzimas depende de su flexibilidad estructural y su variable afinidad inica regulada por factores fisicoqumicos intrnsecos y ambientales, as como una manopla de baseball puede tomar pelotas de distinto tamao... 20. Se identific la formacin de complejos de acarreadores mviles con cationes mono, di y trivalentes; se distinguieron las caractersticas de flexibilidad estructural de los complejos; se determinaron las variaciones de afinidad inica; y se discriminaron los eventos fisicoqumicos que conforman la regulacin de la translocacin inica catalizada. Estos factores pueden resumirse en la expresin general Ji = f(pHamb, pKa, ai, aei, Ei, ri, qi, [A]m, FA, mA, Ks, CpL, DL, mm, Kd) Todo esto guarda correlaciones variadas con su capacidad para atrapar y liberar cationes en procesos metablicos y muestra las caractersticas sistmicas estructurales y energticas que proveen a las osmoenzimas su capacidad para regular al metabolismo vectorial.
Science has often been considered to be the search for simplicity. Milton H. Saier Jr.

21. Posteriormente se identificaron, aislaron, reconstituyeron y caracterizaron los acarreadores proteicos antiparalelos predichos por la Teora de Mitchell. Se ha logrado identificar y obtener numerosas protenas con actividad inica antiport. Algunas son altamente especficas por un ion, como el Na+, mientras que otras pueden intercambiar tanto Na+ como K+ por H+. Desde el postulado de Mitchell, los mecanismos del metabolismo energtico se han resuelto desde un punto de vista bioqumico. Se conoce el comportamiento cintico de varias de las isoformas de antiporters inicos. Se han dilucidado las estructuras primaria a cuaternaria de diversas isoformas de protenas antiporter, a travs de estudios espectroscpicos y con tcnicas bioqumicas y de biologa molecular, adems de mtodos de simulacin computarizada. 22. AI momento, hay una imagen general del papel que juegan los acarreadores y los cationes en el metabolismo vectorial de los organismos. Si bien se conocen los mecanismos de regulacin, negativo ante inhibidores y positivo con otros factores, no se ha establecido un mecanismo fsico y qumico general para la translocacin antiport inica catalizada, ms all de la necesidad de un "canal hidroscpico". En el caso de los antiporters Na+/H+, se discute si se trata de canales sencillos o mltiples, la estructura y localizacin de los sitios activos para cada evento, como el cataltico o el sitio de unin al catin. Se sugieren cambios conformacionales en su funcin y, si es as, cmo lo hace?
Entities should not be multiplied beyond necessity. William of Occam

23-24. El estudio de antiporters se ha encontrado con una diversidad de isoformas en rganos y tejidos 4

de plantas y animales (p.ej. las NHE-1 a NHE-6 en Homo sapiens), as como en protistas y archaeas, que se presentan en variedades diferentes a lo largo de toda la escala filogentica. Se consideran como protenas de membrana de distribucin universal aunque no se han identificado homologas significativas entre protenas de relacin filogentica distante, por lo que se sugeriere que no existen sitios universales de unin Na+/H+ o que pocos residuos son adecuados para el intercambio inico y estn dispersos por la protena. 25. Sin embargo, se deben tomar en cuenta dos consideraciones: 1) los principios de divergencia y convergencia evolutiva y 2) la posibilidad de un modelo qumico o uno fisicoqumico, respectivamente. 26. El estudio estructural primario y helicoidal de isoformas del antiport Na+/H+ con este enfoque ofrece resultados sugerentes. Se identifican diez segmentos transmembranales que persisten y sugieren presencia de un segmento ms en el extremo NH2 en mamferos y uno, del Fen428 al Ile450, en cangrejo azul. Este segmento equivalente en mamferos es hidrofbico/polar y altamente conservado, as como los segmentos 9 y 12; los ms variables son el 7 y el 10, mientras los restantes presentan una variabilidad similar en residuos. El alineado de secuencias muestra poca variabilidad en polaridad de los segmentos 3, 4, 8, 9 y 12, as como alta conservacin de residuos hidrofbicos y polares, tanto aninicos como con -. Es notable la alta conservacin de residuos bsicos en posiciones transmembranales y plasmticas equivalentes del alineado. El anlisis muestra diferencias entre variabilidad qumica (residuos) y fisicoqumica (polar/no polar) y sugiere un patrn de residuos para la unin y translocacin catinica en los NHE de mamferos, por lo que la homologa y la analoga deben jugar papeles importantes, tanto por evolucin divergente como convergente, 27. que deben confirmarse extendiendo el estudio a la mayor amplitud de la escala filogentica. 28. http://www.izt.uam.mx/cosmosecm/BIOFISICOQUIMICA.html Ha llegado el momento imprescindible en que la va entre la biologa y la fsica sea de doble sentido. Esto fue reconocido desde hace aos y la idea ha ido permeando en la comunidad cientfica. En 1990 se llev a cabo en la pequea poblacin corsa de Cargse una conferencia bajo el nombre de "Biologically Inspired Physics". Este ttulo ha servido de inspiracin a muchos cientficos y la conferencia desat una reaccin en cadena muy benfica que, entre otras cosas, ha llevado a revistas de prestigio internacional como Physical Review E, a invitar a la comunidad a contribuir con artculos de investigacin para su nueva seccin de fsica biolgica. Sin embargo, un gran reto pendiente es que los trabajadores de la nueva disciplina logren incursionar en el terreno de las revistas tradicionales de biologa y puedan mostrar cmo la fsica es de utilidad para los bilogos, partiendo de los datos aportados por la propia biologa. Hoy en da se puede hablar de la fsica biolgica como una realidad. Curiosamente, su aparicin no fue a expensas de la biofsica sino todo lo contrario, en un claro ejemplo de lo que es un efecto cooperativo, ha venido a darle nuevos bros. Como se ilustra en este libro, en Mxico tanto la biofsica, como la fsica biolgica, han alcanzado un nivel de desarrollo comparable con el de cualquier pas del mundo. En esta recopilacin contamos con una muestra de la labor que se desarrolla en nuestras instituciones pblicas de educacin superior. El contenido no pretende abarcar la totalidad del trabajo 5

actual, pero engloba un espectro amplio que va desde la fsica de las mquinas moleculares hasta el anlisis no lineal de series de tiempo, evolucin y ecosistemas, pasando por ejemplos de cristalografa, cdigo gentico, estructura del ADN, plegamiento de protenas, interaccin entre biomolculas, difusin en sistemas biolgicos, etctera. 29. La flexibilidad inica-estructural de los politeres corona son fundamento para la nanociencia y la nanotecnologa. Hierarchical self-assembly process of a multi-channel rosette nanotube. In the bottom left corner is the resulting guanine-cytosine rosette nanotube (red) surrounded by 12 crown ether channels (silver). In the background is a transmission electron micrograph of the same complex. The diameter of each nanotube is 4 nm. See article by Fenniri et al. PNAS Cover illustration April 30, 2002; 99 (Suppl 2)on pages 6487 6492. 30. Biomimicry or biomimetics is the examination of nature, its models, systems, processes, and elements to emulate or take inspiration from in order to solve human 31. Biomimetic Microstructure Formation of High Performance Silk Films and Fibers Biomimetic Inspired Fibers, Materials, and Properties Agency/Branch: DOD/USAF Contract: N/A Award Amount: $99,981.00 Abstract: The complex biological processing and spinning operations used by the silkworm and spider to create silk fibers lead to a morphology that yields exceptionally high combinations of strength, stiffness, and extensibility. In this proposed STTR effort,Foster-Miller will join with Professor David Kaplan and the Biotechnology Center at Tufts University in an effort to produce films from silk that possess unique and tailorable properties for emerging Air Force applications. Professor Kaplan has aworld-class reputation in this area and is an acknowledged expert in the biology and characterization of silk. He will provide the team with technical expertise, laboratory characterization and material for this effort. Foster-Miller has extensiveexperience in lyotropic liquid crystalline polymer processing, the synthetic analog to the biological liquid crystal processing characteristic of natural silks. We will combine this expertise with our knowledge of polymer/solvent interactions to mimic thebiomacromolecular assembly of spider silk. In this effort, films will be formed and oriented using a variety of processing techniques to demonstrate proof of concept. The methods developed and lessons learned on this effort can then be adapted andapplied to the processing of high performance fibers in a subsequent Phase II effort. (P-01524) This program pursues broad materials technology development toward general implementation rather than an application-specific development. It is initiallyenvisioned that bulletproof vests and parachute cords present military applications with good near- term pull. Ultimately, the material is likely well suited for highly optimized large space structures such as solar sails or space telescopes, applicationswhere Foster6

Miller is currently working on large deployable structures for the Air Force and NASA. In the commercial marketplace, preliminary target applications certainly include bulletproof vests as well as high strength cords and straps, prostheticdevices, and highly abrasion resistant textiles 32. Rotation of the gamma subunit of thermophilic F1-ATPas was observed directly with an epifluorescent microscope. The enzyme was immobilized on a coverslip through His-tag introduced at the N-termini of the beta subunit. Fluorescently labeled actin filament was attached to the gammma subunit Artificial photosynthesis - photochemical water splitting. Objectives of the project. The visionary idea in SOLAR-H is to design, synthesize and characterize large metal-organic catalytic complexes that shall be able to: i) absorb light; ii) use the light to form an energy rich so called charge separated state; iii) use this stored energy to split water (oxidize water) into hydrogen and oxygen. If efficient photo-catalytic chemistry with these properties could be accomplished and incorporated into a technical device this might become an important future energy supply. Figure 2. Presentation of how a di-iron center in a hydrogenase (left) is mimicked in a di-iron complex that also is linked to a Ru-center. In the di-iron complex the ligands are not too different from those in the hydrogenase di-iron center. The coupled ruthenium-di-iron complex on the right is synthesized by Partner 8. The idea is that photo-excitation of the Ru-center shall drive electron transfer to the coupled iron-dimer. 33. Jack W. Szostak Prize motivation: "for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase" The interlude between wrapping up my work in the Department of Plant Physiology and starting as a transfer student in the Department of Biochemistry provided me with the opportunity for an extended vacation and my first trip to Europe on my own. I began with a visit to Cambridge, England where I was very kindly hosted by Professor Poole (for whom I had worked at McGill), who was on sabbatical at the University of Cambridge. I explored the town and was incredibly impressed by the Chapel of King's College and the ethereal music therein. Even more impressive was the famous Laboratory of Molecular Biology at the MRC, where I talked with one of the iconic figures of molecular biology, Sydney Brenner. I was asked to wait for Sydney in his office, which I was surprised to notice held two large desks, both piled to the ceiling with papers. When Sydney arrived he told me about his remarkable new project involving the use of the nematode Caenorhabditis elegans as a model system for developmental gene cs this was an impressive if somewhat painful lesson on the right way to carry forward such an ambitious project.

By the year 2000, I started to pay more attention to fundamental questions related to the origin of life. My interest in the role of compartmentalization and cellular structure in the origin of life was stimulated by discussions with Pier Luigi Luisi and David Bartel. A year of debate led to a synthesis of our views on the roles of genetics, compartmentalization and evolution, which we expressed in our 2001 Nature paper Synthesizing Life (13). This paper catalyzed my entry into the field of membrane biophysics, for I felt that having proposed a model for early cells in which bilayer membranes played a crucial role, it was incumbent on us to show that such models were physically plausible. I have to admit that I was somewhat surprised to find myself working with lipids and membranes, which are remarkably squishy and ill-defined by comparison with nucleic acids. However, in at least one way, the study of membranes composed of prebiotic building blocks such as fatty acids was perfect for me, since this field was filled with important yet technically addressable questions. 34. Astrobiology makes use of physics, chemistry and biology to investigate the possibility of life on other worlds and help recognize biospheres that might be different from the biosphere on Earth. The term exobiology is similar but more specific it covers the search for life beyond Earth, and the effects of extraterrestrial environments on living things