Evening Lectures
Albany Conversation traditionally holds long evening lectures in areas of fundamental interest to structural biology. In 2007, on Wednesday June 20th 8:00 PM, Nobel Laureate Phillip A. Sharp, MIT, will provide a tour de force overview on the roles of RNA in life, visiting the historical transformation from its exclusive role as messenger and bagman to control of expression through its avataras as si and mi RNAs, and its ability to transform life by alternative splicing. June 21st 2007, Thursday at 8:00 PM, Nobel Laureate Hartmut Michel, MPI, Frankfurt, Germany, will elaborate on the intimate details of the structure and mechanism of the respiratory chain complexes and of sodium/proton exchanging enzymes across membranes. Alex Rich of MIT and Wolfram Saenger, Free University of Berlin, Germany will introduce Phil Sharp and Hartmut Michel respectively and chair the corresponding sessions.

Tumor Suppressor Protein p53 & Partner Proteins
The protein p53 is the guardian of the genome. It is at the center of many networks, some of which are shown elsewhere; p53 is inactivated by mutation in 50% of human cancers. And further, how does p53 executes its transactivation functions within the chromatin and nucleosome positioning? Sir Alan Fersht, Univ. of Cambridge, will describe his current studies on the high resolution structures of domains of the protein and their organization. Zippi Shakked, Weizmann Institute, will dwell on the mechanisms by which p53 recognizes a diverse range of DNA targets; she elucidates the mechanisms from her high resolution crystal structures of p53 tetramers bound to DNA. Tali Haran, Technion, describes her recent studies on the relationship between DNA binding, bending and flexibility in the recognition of p53 target sites by various p53 domains. Patric Chene, Novartis, will describe his work on the identification of molecules that prevent the interaction between p53 and the hdm2 protein as a strategy to stimulate p53 activity in tumor cells. Victor Zhurkin, National Institutes of Health, argues that a stably positioned nucleosome can facilitate the p53 binding by exposing the cognate DNA site in the bent conformation favorable for the p53-DNA recognition; the strongest p53 sites (immediately activating the cell cycle arrest genes) are surrounded by the nucleosome-positioning sequences, while the weak p53 sites are localized within or next to CpG islands known to be sliding-prone regions for nucleosomes.

Biomolecular Machines
We take a close look at some of the fine tuned machines driving the biological system to life. Nobutaka Hirokawa, Univ. of Tokyo, Japan, presents cryo EM and X ray crystallography studies on kinesin superfamily molecular motors, the KIFs, involved in the transport along microtubule rails of various membranous organelles such as mitochondria, molecular motors moving processively by biased Brownian movement. Thomas Steitz , Yale, after having unraveled the structures of enzymes involved in replication, recombination, transcription and protein genesis, dwells on the motion in the functioning of macromolecular machines and presents tour de force motion pictures of the various processes. Joachim Frank, Wadsworth Labs, employs cryo EM to delineate the mechanism of mRNA-tRNA translocation, and to track the conformational changes both in the ribosome and in the elongation factors upon GTP hydrolysis. Patrick Cramer, Univ. of Munich, Germany, will summarize the structural data on the central machine for gene transcription in eukaryotes, RNA polymerase II, in various functional states. In addition, he will discuss the coupling between the transcription process and other nuclear events, including RNA processing, chromatin modifications, and DNA repair. The replicative DNA polymerase machine is the subject of the lecture by Kosuke Morikawa, Osaka Univ., Japan. Using the combined approach of crystallography and EM, Morikawa unfolds important and novel structural phenomena in the ATP dependent clamp loading mechanism.

Evolution: In Search of the Holy Grail
Visiting the past and transporting to the future border on Divinity. We do this in Albany to energize the intellect and pay homage to our ancestral genes. Paul Schimmel, Scripps, explores the origin of human diseases. In the early development of the genetic code, statistical proteins were prominent. Experiments creating statistical proteins from a more primitive code yield phenotypes in mammalian cells that could explain the origin of some human diseases. Ernesto Di Mauro, Univ. of Rome, Italy, operates under the optimism that life is a robust phenomenon, and its origin is likely to have been based on robust chemistry of the one-carbon compound formamide which yields all the necessary precursors under moderate heat in the presence of common catalysts and provides the appropriate thermodynamic niches for the survival of informational polymers once formed. Edward Trifonov, from the ancient city of Haifa, Israel (Univ. of Haifa) looks at the dark subterranean recesses of evolution, the earliest proteins in evolution, evolutionary chart of codons and codes ( a la Da Vinci?), the omnipresence of certain motifs, prototype closed loops and major nodes of sequence, the holy grail of protein evolution. And from the electric and eclectic city in India, Bangalore, we have Ramanathan Sowdhamini, from India's National Center for Biological Sciences, talking about family relationship among proteins, the superfamilies, areas of distant relationships and kinships as they evolve to fabricate and stitch the matrix of life.

Metal Coordination and Hot Wired DNA
Stephen J. Lippard, MIT, plans to talk about structural and functional studies of cisplatin & related complexes bound in a site-specific manner to DNA in a histone reconstituted nucleosome. Included will be hydroxyl radical footprinting experiments as well as studies of nucleosome excision repair & transcription inhibition. Jackie Barton, Caltech, discusses the use of metallointercalators in probing long range DNA charge transport chemistry and, thinking out of the box and unconventionally, how DNA repair proteins containing metal centers may also utilize metal redox centers for long range DNA-mediated signaling. Bengt Nordén, Chalmers Univ. of Tech., Gothenburg, Sweden, lectures on novel DNA ligands, including substitution-inert stereospecific Ru(II) polypyridyl compounds and peptide nucleic acids. Recently he has discovered an extremely slow reorganization process (weeks) of a binuclear ruthenium complex, from a groove-bound state on DNA to a threading intercalating geometry, and with an even slower dissociation rate. Cynthia J. Burrows, Univ. of Utah, takes up DNA damage mediated by transition metals. The heterocyclic bases of DNA are both sensitive to oxidative damage as well as excellent sites for interaction with redox-active transition metal complexes. Depending on the mechanism, unusual oxidized structures are generated presenting challenges for DNA replication and repair.

Innovations: New Implications for Medicine
Valentin V. Vlassov, Russian Academy of Sciences, Novosibirsk, will talk about artificial ribonucleases, small conjugates useful for preparation of antiviral vaccines, designed to mimick active sites of natural enzymes. Ken Douglas, Univ. of Manchester, UK, presents a high resolution approach to signal mutations in cytochrome 450, SNPs etc. The technique involves harvesting exciplex signals & has a potential resolution of a single base pair. Xianglei Yang, Scripps, has exciting x-ray and functional work on the cytokine activities of two human tRNA synthetases, going into clinical trial, beautiful example of how basic studies on genetic code lead to new insights in medicine and disease. Xianglei Yang will discuss the role of the two synthetases in translation and angiogenesis. Chuan He, Univ of Chicago, will present the regulation of antibiotic resistance and virulence in Staphylococcus aureus. Mechanism of this regulation which encompasses the activation of several hundred genes will be presented.

Progress in Bioinformatics and Structural Computing
Eugene I Shakhnovich, Harvard Univ., presents advances in ab initio all-atom folding simulations that make it possible to simulate folding of small proteins from sequence to near-native structure with acceptable resolution (2-5Å). In the process he also obtains ensemble description of their folding pathways at atomic resolution. B. Jayaram, from IIT, New Delhi, India- this is the extraordinarily inviting, gorgeous, romantic city of ancient mogul architecture, steeped in culture, grace and opulence, next door to Taj Mahal where we wanted to hold this 15th Conversation, and, touch spirituality, but the terrorists drove us away to Albany - advances a novel semi-empirical formalism, based on physico chemical perspectives, for whole genome analysis, protein structure prediction and drug design. Richard Bryce, from the Univ. of Manchester, UK, discusses new computational strategies for modeling the complex structure and dynamics of carbohydrates based on semi-empirical quantum mechanical methods. Remo Rohs, currently at Columbia, applies new computational approaches to address the selection, formation and stabilization of complexes between DNA and proteins or drug molecules. The prediction of intrinsic and induced structural effects such as DNA bending and A/B-DNA transition states is combined with the analysis of structural and energetic origins of binding. Manju Bansal, Indian Institute of Science, Bangalore, India, shows that the promoter regions in both prokaryotic and eukaryotic genomes have distinct structural signatures such as curvature and bendability vis-a-vis their neighboring regions. Based on this she develops a formalism at the genomic level to identify the promoter regions. While structures are indispensable for understanding how these macromolecules act, other, less visible properties can also play a role in determining function. Richard Lavery, IBPC, Paris, France, takes up the question of macromolecular mechanics and function, and demonstrates using molecular simulations, how highly heterogeneous mechanics can play a significant role in both their catalytic and interactive behavior.

RNA: Catalysis, Structure, Interactions and Dynamics
David Lilley, Univ. of Dundee, dwells on the VS ribozyme, the largest of the nucleolytic ribozymes. This consists of five helical sections organized by two three-way junctions, each of which undergoes metal ion-induced folding. The folded structure binds the substrate stem-loop, generating a catalytically-productive interaction. Joe Piccirilli, Univ. of Chicago, presents beautiful chemistry on RNA catalysis, using phosphorothiolates to demonstrate acid catalysis, to reveal the transition state interactions in the HDV ribozyme. This is classic. Juli Feigon, UCLA, works with the large ribonucleoprotein complex telomerase, activity of which is correlated with both aging & most cancers. Juli presents the NMR based structural biology of telomerase, providing insight into its function and the effect of mutations in the RNA linked to disease. Peter Varnai, Univ. of Cambridge, UK shows how NMR data can be used as restraints in molecular simulations to obtain conformational ensembles consistent with the structure and dynamics of the RNA system simultaneously.

Protein-Protein Recognition: Living Cell NMR, Virus Avatara & Signaling.
Alexander Shekhtman, SUNY at Albany, has developed an in-cell NMR-based method for mapping the structural interactions that underlie protein-protein complex formation. This method entails sequentially expressing two (or more) proteins within a single bacterial cell and monitoring their interactions at atomic resolution. Jacob Anglister, Weizmann, Israel shows that the V3 region of the envelope glycoprotein (gp120) of HIV-1 determines the phenotype of the virus. NMR structures of V3 peptides bound to HIV-1 neutralizing antibodies reveal two alternative conformations of the V3 and decipher the mechanism of the conformational switch leading to phenotype conversion. David Fushman, Univ. of Maryland, discusses the results of his NMR studies of the conformation, dynamics, and ligand binding properties of Lys48- and Lys63-linked polyubiquitin chains which provide structural evidence that diversity in ubiquitin-mediated signaling arises from linkage-specific conformational differences between alternatively linked polyubiquitin chains.

Channels, Membrane Proteins & Signal Transduction
Yoshinori Fujiyoshi, Kyoto Univ., Japan, will discuss structure & function of channels, the membrane proteins being analyzed by an originally developed electron cryo-microscope; his method enables to clarify the mechanisms of multifunctional channels such as water and ion channels. David Lambright, Univ. of Mass. Medical Schl, is developing a systems approach to molecular recognition in the RabGTPase family - critical master regulators of membrane traffic with some 60 proteins - to unravel the non-phylogenetic encoding of specificity that allows homologous as well as non-homologous effectors & regulatory factors to achieve highly selective recognition of small, & in some cases overlapping, subsets of Rab GTPases. Richard Neutze, Chalmers Univ. of Tech., Gothenburg, Sweden, uses x-ray diffraction to understand the structural mechanisms of membrane protein, such as gated aquaporins, or energy tranducing systems such as the bacterial rhodopsins & photosynthetic reaction centers.

DNA: Not Merely the Secret of Life
Ned Seeman, NYU, who single handedly invented the field of DNA nanotechnology, discusses the use of branched DNA with cohesive ends. This has enabled him to make objects, lattices and nanomechanical devices. Recently, they have begun to use DNA to organize other species, such as metallic nanoparticles, DNAzymes and nanomechanical devices into arrays. Dipankar Sen, Simon Fraser Univ., Canada, shows the versatility of guanine quadruplex motifs within DNA, or mismatched motifs capable of forming quadruplexes, in forming and modulating DNA-based nanostructures. Hao Yan, Arizona State Univ., will present his recent experimental progress at ASU to utilize DNA nanostructures for self-assembly as well as for templates in the fabrication of functional nano-patterned materials. Milan Stojanovic, Columbia Univ., will describe a modular approach to molecular computation based on catalytic nucleic acid enzymes. The versatility of the approach will be demonstrated through an example of an automaton consisting of 128 molecular logic gates playing perfectly a complete game of tic-tac-toe. He will also discuss the potential of molecular computation to control the rate and direction of diffusion of molecules in what is arguably an approach to molecular robotics.

DNA Structural Motif, Disease and Death: Real or House of Cards?
Is there a real relation between DNA motif & human disease? Or is one building a house of cards? Alex Rich, MIT, discusses "Host vs Virus: The Z-DNA Strategy of Pox Viruses" where he dwells on the virulence factor in vaccinia virus. Structure-prone DNA repeats, including those implicated in human hereditary disorders, stall the replication fork progression in vivo. This stalling is likely due to the formation of unusual DNA structures in the course of DNA replication, argues Sergei Mirkin, Univ. of Illinois, Chicago. He discusses the role of repeat-caused replication stalling in genome instability, including expansions, deletions & chromosomal rearrangements. DNA three-way junctions may form as intermediates in triple repeat sequences associated with many diseases, for instance Huntington's disease. Sybren Wijmenga, Radboud Univ. Nijmegen, The Netherlands, presents NMR solution 3D structures of branched DNAs, three & four-way junctions, providing insight into the sequence determinants of their complex folding & function.

Structural Genomics
Udo Heinemann, MDC, Berlin, Germany, will be describing new approaches to proceed from the systematic structure analysis of single human proteins to the structural characterization on protein complexes, using proteins involved in vesicle transport as an example. Soichi Wakatsuki, KEK, Japan, describes the structural proteomics on intracellular transport of proteins & lipids, protein glycosylation & carbohydrate recognition using state-of-the-art synchrotron radiation protein crystallography. Gaetano T Montelione, Rutgers Univ., dwells on the structural proteomics achievements of eukaryotic domain families at the Northeast Structural Genomics Consortium (NESG) which is one of four Large-Scale Protein Structure Production Centers under NIH. The goals of the NESG project include determining some 1,000 3D protein structures over ten years. Technologies for high-throughput structure production, including robotic methods of sample preparation & methods for rapid NMR data collection & analysis, have been developed by the NESG.