Phasing Out Theoretical Model Depositions to the PDB Archive

Effective October 15, 2006, PDB depositions will be restricted to atomic coordinates that are substantially determined by experimental measurements on specimens containing biological macromolecules. This policy was recommended and endorsed by a working group comprised of structural and computational biologists and endorsed by the wwPDB advisory committee. Thus, theoretical model depositions (such as models determined purely in silico using, for example, homology or ab initio methods) will no longer be accepted.

Theoretical models that have been previously released or that will be released from now until October 15, 2006 will continue to be publicly available via the existing models archive at ftp://ftp.rcsb. org/pub/pdb/ data/structures/ models/current/.

A summary of the implementation plan for the phasing out of theoretical models is available in HTML and PDF formats. A paper describing the outcome of the Workshop on Archiving Structural Models of Biological Macromolecules will be available in the August 16 issue of Structure1.

Questions about this transition should be sent to info@wwpdb.org.

Systems Biology: the 21st Century Science

Systems biology is the study of an organism, viewed as an integrated and interacting network of genes, proteins and biochemical reactions which give rise to life. Instead of analyzing individual components or aspects of the organism, such as sugar metabolism or a cell nucleus, systems biologists focus on all the components and the interactions among them, all as part of one system. These interactions are ultimately responsible for an organism´s form and functions. For example, the immune system is not the result of a single mechanism or gene. Rather the interactions of numerous genes, proteins, mechanisms and the organism´s external environment, produce immune responses to fight infections and diseases.

Systems biology emerged as the result of the genetics "catalog" provided by the Human Genome project, and a growing understanding of how genes and their resulting proteins give rise to biological form and function.

A traditional approach to studying biology and human health has left us with a limited understanding of how the human body operates, and how we can best predict, prevent, or remedy potential health problems. Biologists, geneticists, and doctors have had limited success in curing complex diseases such as cancer, HIV because traditional biology generally looks at only a few aspects of an organism at a time.

The individual function and collective interaction of genes, proteins and other components in an organism are often characterized together as an interaction network. Indeed, understanding this interplay of an organism´s genome and environmental influences from outside the organism (nature and nurture) is crucial to developing a — systems — understanding of an organism that will ultimately transform our understanding of human health and disease.Systems biology is still in its infancy; we are at the turning point in our understanding of what the future holds for biology and human medicine.

Pharmacogenomics and personalized medicine: mapping of future value creation

People have been talking about personalized medicine, to a point that it almost gets old. Some are firm believers in this revolution and are actively devoting effort to advance it, others wonder whether this is yet another hype, and yet many others may have an impression that, as promising a future as it paints, it may only become reality in another lifetime.Personalized medicine addresses current unfilled needs in the healthcare world by calling for the right treatment for the right individual at the right time. In current drug therapeutics world, it is widely observed that a drug doesn't work for all the patients all of the time. Drugs do not have the desired outcome in 30%–40% of patients, blockbuster drugs are often efficacious in 40%–60% of the patients, and it is not unusual to see chemotherapy working for only 30% of cancer patients (from industry expert interviews, the American Medical Association. In addition, drugs can at times cause adverse drug reactions (ADRs), with some more severe than others.

There are different levels of variation among individuals that could account for the varying outcomes of drug therapy, such as patients' different drug absorption, distribution, metabolism, and excretion (ADME) profiles measurable at organ, tissue, or cellular levels and more fundamental differences at molecular levels, [i.e., analyses of protein, RNA (gene expression analysis), and DNA (genotyping)]. Genotyping and gene expression analysis are current key component technologies of pharmacogenomics (PGx) that currently serves as the major driving force for the personalized medicine revolution.

PERSONALIZED MEDICINE: WHEN WILL IT HAPPEN?

Nanoarrays

Scientists have developed a new type of protein array for studying interactions between proteins and other molecules on an extremely small scale. Size is what sets these arrays apart—they are built on a nano-scale (one nanometer equals one-billionth of a meter). The arrays are coated surfaces containing proteins that can be exposed to other proteins and structures in order to study their interactions.

"The ability to make protein nanoarrays on a surface with well-defined feature size, shape, and spacing should increase the capabilities of researchers studying the fundamental interactions between biological structures (cells, complementary proteins, and viruses) and surfaces patterned with proteins," the researchers write in Science Express. Chad A. Mirkin, of Northwestern University in Evanston, Illinois, led the research.

The method used to create the protein nanoarrays is called dip-pen lithography. This technique involves using an instrument to modify the surface of the arrays, which is a type of gold film. The dip-pen lithography allows researchers to create high-resolution patterns on the surface, thereby giving the arrays their sensitivity.

In a related study, Mirkin and two colleagues at Northwestern's Institute for Nanotechnology developed a new method of detecting small amounts of DNA in a solution. The method relies on an electrical current to indicate the presence of complementary strands of DNA. When complementary DNA strands bind, gold nanoparticles form a bridge that conducts an electric signal. A photographic solution containing silver can be added to further amplify the signal.

The Backrub Motion: How Protein Backbone Shrugs When a Sidechain Dances

Surprisingly, the frozen structures from ultra-high-resolution protein crystallography reveal a prevalent, but subtle, mode of local backbone motion coupled to much larger, two-state changes of sidechain conformation. This “backrub” motion provides an influential and common type of local plasticity in protein backbone. Concerted reorientation of two adjacent peptides swings the central sidechain perpendicular to the chain direction, changing accessible sidechain conformations while leaving flanking structure undisturbed. Alternate conformations in sub-1 Å crystal structures show backrub motions for two-thirds of the significant Cβ shifts and 3% of the total residues in these proteins (126/3882), accompanied by two-state changes in sidechain rotamer. The Backrub modeling tool is effective in crystallographic rebuilding. For homology modeling or protein redesign, backrubs can provide realistic, small perturbations to rigid backbones. For large sidechain changes in protein dynamics or for single mutations, backrubs allow backbone accommodation while maintaining H bonds and ideal geometry