Wed, 31 Mar 2010 23:10:11 -0400 http://www.proteindesign.com/ Protein Design http://www.proteindesign.com/images/ http://www.proteindesign.com/ davidyee@yahoo.com http://www.proteindesign.com/a-100.html How the Heart Works: A Basic Overview by David Yee (Originally Written 10-5-1994) I. Location A. the heart is located in the chest; it lies left of the body's midline, above and in contact with the diaphragm B. situated immediately behind the breastbone, or sternum, and between the lungs, with apex tiled to the body cavity's left side II. Heart has two cavities, divided by the cardiac septum A. Right cavity takes in oxygen poor blood from the body and pumps it to the lungs 1. has an atrium (collecting chamber) and a ventricle (pumping chamber); atrium is on top of ventricle a. atrium draws blood from veins, and ventricle pushes blood into arteries b. thin walls for atrium and thick walls (=3x walls for atrium) for ventricle 2. has tricuspid (an atrioventricular valve) and pulmonary (a semilunar valve) valves B. Left cavity takes in oxygen rich blood from the lungs and pumps it to the body 1.Same as A1, except walls are 2x as thick 2. has mitral (an atrioventricular valve), 2 flaps, also called bicuspid valve and aortic (a semilunar valve) valves III. Two stages in each heartbeat cycle: diastole and systole A. Diastole 1. Heart muscle relaxes, blood is thus drawn into the two atria from veins. a. oxygen-poor blood into the right atrium from major veins superior and inferior vena cava; each through a separate opening b. oxygen-rich blood into the left atrium from four pulmonary veins (2 from each lung) 2. Rising pressure in each atrium opens the tricuspid and mitral valve and blood flows into the ventricles. B. Systole 1. Sinoatrial (SA) node fires impulses, stimilating atria to contract. 2. All the blood are forced into the ventricles 3. Mitral and tricuspid valves close due to rising pressure in ventricles. 4. Ventricles fully contract. 5. Aotric and pulmonary valves are forced open. 6. Blood pushes out to the arteries (aorta and pulmonary arteries). 7. Heart relaxes, and the aortic and pulmonary valves close. Return to diastole. V. Additional information A. Amount of blood pumped 1. At rest, the heart pumps about 59 cc (2 oz) of blood per beat and 5 l (5 qt) per minute 2. During exercise, 120-220 cc (4-7.3 oz) per beat and 20-30 l (21-32 qt) per minute B. Size 1. The adult human heart is about the size of a fist and weighs about 250-350 gm (9 oz). 2. Thickness of heart muscles varies from 2 mm to 20 mm C. Heart's wall has three layers 1. The outer layer of the heart is called the epicardium. a. is in intimate contact with the pericardium (a serous membrane that is a closed sac covering the heart muscle's outside wall). Within the sac, a small amount of fluid reduces the friction between the two layers of tissue. 2. The middle layer is the myocardium (heart muscle) 3. The inner layer is the endocardium a. consists of a thin layer of endothelial tissue overlying a thin layer of vascularized connective tissue Wed, 31 Mar 2010 23:10:11 -0400 http://www.proteindesign.com/a-99.html EGAD is a free open-source program for protein design and mutant prediction. EGAD's main focus is performing protein design on fixed backbone scaffolds. It can also consider multiple structures simultaneously for designing specific binding proteins or locking proteins into specific conformational states. In addition to natural protein residues, EGAD can also consider free-moving ligands with or without rotatable bonds. It may even be possible to use EGAD for drug design. EGAD can be used with a single processor, but it can take advantage of the power of parallelization to perform certain jobs quickly. Some of the tasks EGAD can perform are: prediction of mutation effects on protein stability and protein-complex formation to within ~1kcal/mol, automated scanning mutagenesis, including saturation mutagenesis, of proteins and protein complexes, total protein sequence design, design of ligand binding sites, optimization of sequences while considering multiple structures for the design of specific binding proteins and conformational switching, predicting the pK's of ionizable groups in proteins, and generating tables to display the distribution of energetic interactions in protein structures. Thu, 03 May 2007 16:27:07 -0400 http://www.proteindesign.com/a-98.html Ashley from Monash University in Australia would like to announce that the group she is working with have released a new version of the Protein Folding Database at http://www.foldeomics.org/pfd/. "The database aims to collect all folding data into one repository and, within the framework of the International Foldeomics Consortium (http://www.foldeomics.org), encourage sharing and data analysis. We are particularly interested in allowing the graphical analysis of raw-data on the site." You can register to do advanced searches and to submit your own protein folding data. Thu, 12 Oct 2006 02:32:06 -0400 http://www.proteindesign.com/a-97.html [excerpt] Proteins are major players in the biological world—among other things, they make biochemical reactions go and serve as building blocks for much of the structural elements of organisms. But before any protein can fulfill its biological role, it must fold itself into its designated shape, or conformation. Incorrectly folded proteins don’t work and diseases such as Parkinson’s, Huntington’s and mad cow are all associated with misfolded proteins that clump together. While it is generally understood that proper protein folding happens spontaneously, scientists are still trying to understand what causes a particular protein to fold properly or go awry. The protein’s local environment plays a role, and other molecules in the neighborhood can assist or hinder the process, says Gierasch. “It’s a delicate balance—proteins can tip to the dark side very readily,” she says. Recently researchers have developed techniques that allow them to follow the fate of individual proteins within cells. Using an experimental set-up that they designed to do just that, Gierasch and Ignatova decided to see how the small molecule proline influenced protein folding. Proline is often taken up by cells in response to water loss, and other molecules with similar cellular roles have been shown to inhibit improper folding. “There have been conflicting results,” says Gierasch, “In some cases these molecules inhibit misfolding, in some cases they promote it.” Fri, 11 Aug 2006 15:07:41 -0400 http://www.proteindesign.com/a-96.html [excerpt] The new anti-amyloid agent eprodisate sodium (NC-503) is safe and exerts a clinically meaningful and statistically significant effect on amyloid A (AA) amyloidosis that can result in loss of tissue and organ function in patients with underlying inflammatory conditions, according to a combined international, multicenter, randomized, double-blind, placebo-controlled, phase 2/3 trial. This study was presented here on June 23rd at the Annual European Congress of Rheumatology (EULAR) on behalf of the Fibrillex Amyloid Secondary Trial (FAST) Group by Bouke P.C. Hazenberg, MD, coinvestigator and consultant in rheumatology, rheumatology, and clinical immunology at the University Medical Centre Groningen in Groningen, The Netherlands. Amyloidosis is a protein-folding disorder that can occur in diseases characterized by extracellular deposition of insoluble fibrillar proteinaceous material, thereby resulting in loss of function of the tissue or organ involved. Thu, 13 Jul 2006 21:55:31 -0400 http://www.proteindesign.com/a-95.html [excerpt] Studying receptors on the surface of blood platelets, sticky cells that cause blood to clot, has given one Rockefeller researcher new insight into potential causes and treatments for certain cardiovascular diseases. Barry Coller, David Rockefeller Professor and the university’s physician-in-chief, has been focusing on a rare disorder known as Glanzmann thrombasthenia, in which platelets lack one of two proteins. Together, the two proteins — αIIb and β3 — create a cellular receptor that’s involved in aggregating blood cells for coagulation; analyzing patients with the disorder previously led Coller to develop a novel therapy for heart-attack and stroke victims that targets this receptor. Wed, 31 May 2006 13:13:55 -0400 http://www.proteindesign.com/a-94.html [excerpt] Interestingly, small but simple structures like atoms can exhibit well-behaved motion, and have been studied extensively for applications such as MRI (more precisely, Nuclear Magnetic Resonance Imaging). The MRI instrument detects tissue density in living things by mapping the presence of Hydrogen in water — tissue density is related to water density, which is related to Hydrogen density. We detect Hydrogen atoms by exciting them at their resonant frequency of 42,580,000 Hz. In between the size of an atom and a drop of water, objects the size of living cells would be expected to vibrate mechanically at intermediate frequencies (10,000-500, 000 Hz). But also consider that other oscillations besides mechanical shaking are of interest in cells, including the rate of protein folding and unfolding, the rate at which nutrients enter and leave a cell, the rate at which life processes take place, and many others. Wed, 31 May 2006 13:10:03 -0400 http://www.proteindesign.com/a-93.html [excerpt] Misfolded and damaged proteins are common to all human neurodegenerative diseases. Clumps of these aggregated proteins destroy neurons within the brain and cause disease. But explanations for the mechanism that actually causes cell death have varied widely, puzzling scientists and leading them to ask whether Alzheimer's, Parkinson's, Huntington's and Creutzfeldt-Jakob diseases and familial amyotrophic lateral sclerosis are related diseases or very different diseases. Researchers at Northwestern University have offered a clue that may get to the core of the cell death question and establish a common mechanism in these diseases. In a study, published in the journal Science, the research team showed that polyglutamine ( the toxic component of the protein responsible for Huntington's disease ) is so demanding on the cell's system that it changes the environment within the cell, causing other metastable, or partially folded, proteins to crash and lose function. Over time, this can cause the organism to die. " Our results suggest that these disease-associated, aggregation-prone proteins may exert their destabilizing effects by interfering generally with other proteins that are having difficulty folding," said Richard I. Morimoto, who led the study. Wed, 31 May 2006 13:02:33 -0400 http://www.proteindesign.com/a-92.html [excerpt] Interactions between proteins are the engines that drive the lives of cells, and a better understanding of these relationships -- and the structures that enable them -- are the next great frontier in the biological sciences. Now, a discovery by Weill Cornell Medical College researchers is changing decades-old conventional wisdom on the "coiled coil," a common protein structural motif scientists thought they knew well. The finding, recently published in the journal Structure, marks an incremental but important advance in understanding the complex, three-dimensional interactions between these building blocks of life. "A deeper knowledge of these types of relationships is crucial, because it gets us a tiny step closer to recreating them artificially -- using 'designer proteins' to treat and even cure disease," explains senior author Dr. Min Lu, Associate Professor of Biochemistry at Weill Medical College of Cornell University, New York City. While the sequencing of the human genome was justly hailed as a milestone, it may prove to be just a stop on the way to a much bigger prize -- protein engineering. "Remember, genes are simply the code that cells use to make proteins," Dr. Lu explains. Every day, the body creates tens of thousands of different proteins that fold together in complex, three-dimensional ways to perform specific functions. "Understanding, fixing, and even reproducing these interrelationships is really the next scientific frontier, with infinite possibilities for the health sciences and beyond. Right now, however, we know very little about the way proteins fold," he says. Fri, 14 Apr 2006 16:47:40 -0400 http://www.proteindesign.com/a-91.html [excerpt] A team of researchers from EPFL, (Ecole Polytechnique Fédérale de Lausanne), the University of Lausanne, Northwestern University and Tel Aviv University bring biology and statistical physics together to answer the question of how molecular chaperones fold, unfold and pull proteins around in the cell. Their results appear the week of April 3 in the advance online edition of the Proceedings of the National Academy of Sciences. A series of discussions in a campus café in Lausanne has blossomed into an extraordinary collaboration between EPFL physics professor Paolo De Los Rios and University of Lausanne biology professor Pierre Goloubinoff. Using the principles of statistical physics, they have identified a simple, single mechanism that explains the mechanical role of molecular chaperones in protein folding and translocation, settling at the same time a long-standing controversy over this process. Fri, 14 Apr 2006 16:45:31 -0400 http://www.proteindesign.com/a-90.html [excerpt] Plants as biofactories Using plants, it is technically possible to grow, harvest, and process pharmaceutical proteins on a large scale. The genetically modified crop containing edible vaccine, for instance, can be consumed raw or partially processed. By targeting protein expression into specific organs of the plant such as grains, one creates a stable storage system. By targeting the recombinant protein to subcellular regions of the cells, such as the endoplasmic reticulum, a favorable environment is created for its appropriate folding and assembly, thus increasing the amount of recombinant proteins produced. Additionally, targeting the recombinant protein to the membrane concentrates the product. As a consequence, the cost of downstream purification is minimized. Finally, using plants for the production of drugs reduces the risk of contamination with human or animal pathogens, unlike production via animal or human sources. So far, pharmaceutical proteins produced in plants can be classified into three groups: human biopharmaceutical proteins, including growth hormone, human serum albumin, β-interferon, and erythropoietin; recombinant antibodies such as IgG1 and IgM; and recombinant subunit vaccines, from the hepatitis B envelope proteins and the rabies virus glycoproteins to the cholera toxin B subunit. Sun, 12 Mar 2006 02:51:20 -0500 http://www.proteindesign.com/a-89.html [excerpt] Vitamin E – good or bad – has been a hot topic in medicine for the last couple of years. New research at Ohio State University, looking at how two forms of vitamin E act inside animal cells, has concluded this powerful antioxidant, popular with senior citizens, is "truly a double-edged sword." In the past couple of decades, a slough of studies has looked at the benefits of vitamin E and other antioxidants. While a considerable amount of this research touts the advantages of consuming antioxidants, some of the studies have found that in certain cases, antioxidants, including vitamin E, may actually increase the potential for developing heart disease, cancer and a host of other health problems. This study provides clues as to why this could happen, say Jiyan Ma, an assistant professor of molecular and cellular biochemistry, and his colleague David Cornwell, an emeritus professor of molecular and cellular biochemistry, both at Ohio State. Tue, 07 Mar 2006 00:09:42 -0500 http://www.proteindesign.com/a-88.html [excerpt] One by one, they slightly "mutated" the normal arrangement of atoms in proteins to effectively delete hydrogen bonds at five analogous positions along the structural "backbones" of two different protein molecules that fold in the same pattern. Then they analyzed how each deletion affected the stability of the protein. "Stability" means how low energy, or "relaxed," the protein was. "We deleted each hydrogen bond and then measured how relaxed the protein was afterwards," Fitzgerald said. "It turns out we destabilized the structure in each case. So the relaxed state was not so relaxed any more. The proteins were more stable with those hydrogen bonds. "Those bonds seemed to clearly play a role in protein folding. And what we were able to uncover in this work is that this role may be highly conserved in a protein fold." With Wang as the first author, the three chemists described their results in a paper published online on Friday, Feb. 10, 2006 in the journal Proceedings of the National Academy of Sciences. Their research was funded by the National Institutes of Health. Their paper reported that deletions at each position on one folded protein, known as Arc, had the identical effect at the analogous position on the other protein, called CopG. "Remarkably, the five paired analogs with...mutations at structurally equivalent positions were destabilized to exactly the same degree," the authors wrote. Thu, 23 Feb 2006 12:58:02 -0500 http://www.proteindesign.com/a-87.html [excerpt] Intelligent design should not be taught as a scientific theory. At the core of its character, it is not a science. “Science,” as we use the word in everyday language, is a field that consists of hundreds of years of tested ideas that describe how the world works. Science, in a more formal context, is a method, an approach. The goals of science are to build on what’s known, through new discoveries and correction or clarification of old information. While it’s true that ID theory uses facts of science to support its claims, it has nothing new to report. It only seeks to prove itself. Science doesn’t seek to prove itself, but rather to describe the behavior and character of the universe. ID is a single belief or idea: “an intelligent force had a hand in building and organizing life.” To equate the two by pitting them against one another is ridiculous. It’s like stating a very broad idea, such as, “Fruits and vegetables are nutritious,” and comparing it to the comment, “I like steak.” The latter is a single preference. The former is an evaluative statement with a broader scope. I see no problem with a scientist holding the belief that an overarching intelligent force influenced life. But that belief is personal. It’s for the scientist’s own mind. When the scientist is testing wastewater for chemical compounds, or studying how bees interact with pollinators or even looking at the genetic code of fruit flies, that belief doesn’t factor in. Mon, 13 Feb 2006 01:05:03 -0500 http://www.proteindesign.com/a-86.html [excerpt] Although they are much weaker than the preeminent "covalent" chemical bonds that bind atoms in biological molecules, hydrogen bonds are known to occur at key points along the central "backbone" structures of all folded proteins. The hydrogen bonds are created by attractions between adjacent hydrogen and oxygen atoms that are sandwiched into the molecular framework. How big a role hydrogen bonds actually play in protein folding has been a controversial scientific question, according to Duke associate chemistry professor Michael Fitzgerald. "There's been an ongoing debate about the exact role of those hydrogen bonds," he said in an interview. "Are they really super-important, or are they really negligible?" Fitzgerald, his graduate student Min Wang and his former graduate student Thomas Wales helped address that question in an effort that took years of work. One by one, they slightly "mutated" the normal arrangement of atoms in proteins to effectively delete hydrogen bonds at five analogous positions along the structural "backbones" of two different protein molecules that fold in the same pattern. Then they analyzed how each deletion affected the stability of the protein. "Stability" means how low energy, or "relaxed," the protein was. Mon, 13 Feb 2006 01:01:21 -0500 http://www.proteindesign.com/a-85.html [excerpt] The number of therapeutic proteins is increasing rapidly. Advanced cell-based manufacturing technologies help when it comes to producing recombinant proteins. Protein-based therapeutics is the newest class of chemical compounds being developed by the drug industry, and it is estimated that about 900 to 1,200 clinical candidate proteins and/or peptides are currently being investigated. In addition, 140 therapeutic proteins have been approved and 500 are in clinical trials, and it is expected that at least 50 biotherapeutics will come on to the market over the next few years. Many of these biotherapeutics are produced using technologically advanced cell biosystems. These include microbial and mammalian systems, as well as transgenic plants and animals. These cell-based protein manufacturing technologies offer certain advantages, but they present a number of challenges as well. The use of microbes for human applications is decades old, but the advent of genetic engineering provided the means to produce recombinant proteins in bacteria and yeast, making them productive bioreactors. Wed, 14 Dec 2005 01:35:27 -0500 http://www.proteindesign.com/a-84.html [excerpt] We got a better understanding of biopolymer structural dynamics, which have a large impact in biology and biosecurity,” Laurence said. In the study of proteins, researchers have not quite figured out what causes a protein to go from a folded to unfolded state. But Laurence said the recent study sheds some light on the mystery. The structure in the energy landscape is what encourages it to fold or not to fold,” he said. “You want to see what protein is doing in an unfolded state and why it folds. Then you can understand why the folding sometimes goes wrong.” Laurence said protein folding gone awry can provide some keys to as to why certain people are prone to Alzheimer’s or other neurodegenerative diseases. In addition, understanding how and why protein folds can help scientists design proteins to perform specific tasks. Sat, 19 Nov 2005 23:33:25 -0500 http://www.proteindesign.com/a-83.html [excerpt] Scientists continue to be puzzled by how proteins fold into their three-dimensional structures. Small single-domain proteins may hold the key to solving this puzzle. These proteins often fold into their three-dimensional structures by crossing only a single barrier. The barrier consists of an ensemble of extremely short-lived transition state structures which cannot be observed directly. However, mutations that slightly shift the folding barrier may provide indirect access to transition states. Researchers from the Max Planck Institute of Colloids and Interfaces and the University of California, San Francisco have suggested a novel method to construct transition state structures from mutational data (PNAS, July, 2005). Proteins are chain molecules assembled from amino acids. The precise sequence of the twenty different types of amino acids in a protein chain is what determines which structure a protein folds into. The three-dimensional structures in turn specify the functions of proteins, which range from the transport of oxygen in our blood, to the conversion of energy in our muscles, and the strengthening of our hair. During evolution, the protein sequences encoded in our DNA have been optimised for these functions. Tue, 18 Oct 2005 01:37:23 -0400 http://www.proteindesign.com/a-82.html [excerpt] Osmolytes, whose effects were first well described in 1982, work to preserve various forms of life under extraordinarily hostile conditions. They keep cells alive in human kidneys, for example, despite high concentrations of the protein-destroying chemical urea; they enable a species of frog found in the Arctic literally to be frozen solid and then thawed without harm; and they make it possible for the remarkable microscopic creatures known as “water bears” to survive complete drying, exposure to intense radiation, and temperatures ranging from a few degrees above absolute zero to that of superheated steam. Mon, 10 Oct 2005 20:17:04 -0400 http://www.proteindesign.com/a-81.html [excerpt] The gene for this protein, called p53, is the most commonly mutated gene in human cancer; and it plays a critical role in helping cells respond to stress, especially stresses that damage DNA, according to researchers. Previously, the rise in the level of p53 in cells whose DNA had been damaged was thought to be due only to a decrease in the rate at which the p53 protein is broken down in the cell. The St. Jude study showed that the level of p53 protein synthesis increases following DNA damage. This discovery suggests that scientists can use this newly recognized mechanism to modulate p53 function in the cell in order to control whether cells in the body mutate, and whether cells live or die after DNA damage. A report on this work appears in the October 7 issue of the journal Cell. Mon, 10 Oct 2005 20:07:08 -0400 http://www.proteindesign.com/a-80.html [excerpt] Genistein, a soy extract, inhibits the formation of fibril plaques that interfere with the functions of internal organs. In amyloid diseases, those plaques are formed by the misfolding of a human protein, the scientists reported. Fri, 07 Oct 2005 11:12:50 -0400 http://www.proteindesign.com/a-79.html [excerpt] A problem that has bedeviled biologists for decades is why a chain of amino acids always folds in a specific way. Understanding how proteins fold could lead to the design of new proteins for highly specific functions, or new therapeutic drugs. Researchers Susan Marqusee and Carlos Bustamante decided to investigate this problem one protein at a time. Grabbing both ends of a single protein, they pulled and slowly unbent the protein, then gradually let it relax into its original 3-D shape. Sun, 02 Oct 2005 00:59:50 -0400 http://www.proteindesign.com/a-78.html [excerpt] A protein that provides a vital passage through a bacterium's outer cell wall will misfold and malfunction if that wall is built of the 'wrong' material, scientists at The University of Texas Medical School at Houston report in a finding that has long-term implications for understanding diseases caused by misfolded proteins such as cystic fibrosis, Alzheimer's disease, and mad cow disease. The paper in today's Journal of Biological Chemistry by Professor of Biochemistry and Molecular Biology William Dowhan, Ph.D., and colleagues shows that phospholipids, which make up the permeable barrier of cell membranes, play a direct role in the folding of membrane proteins – proteins that penetrate the membrane or bind to either side of it. "What we've demonstrated again is that it's not just a membrane protein's genetically determined sequence that dictates how it folds so that it can function properly. Its lipid environment also plays a role," Dowhan said. "People used to assume that specific lipids made no difference." In the JBC paper, Dowhan and colleagues looked at how a protein called GabP, which transports an amino acid across the membrane of the bacterium E. coli, is affected by the presence of a phospholipid named phosphatidylethanolamine, or PE for short. Wed, 20 Jul 2005 12:10:01 -0400 http://www.proteindesign.com/a-77.html [excerpt] An international consortium of scientists led by Professor James Paulson of The Scripps Research Institute has created a technology that will advance our understanding of the role of complex sugar chains (glycans or carbohydrates) that decorate the surface of cells in the body. The technology, known as a functional glycan microarray, is a glass slide onto which are printed hundreds of different glycan chains. The array offers scientists a cutting edge research tool allowing them to analyze the specificities of glycan binding proteins (GBP's), which function through their binding to such sugar chains. Sat, 04 Jun 2005 18:41:45 -0400 http://www.proteindesign.com/a-76.html [excerpt] Doctors don't yet understand whether amyloids cause disease or result from it, but the fact that they are present in very different diseases affecting millions of people points to the need for improved understanding of the basic processes of protein folding, one of the most complicated and least understood of all biological phenomena. Research appearing in the Oct. 8 issue of the Journal of Molecular Biology, describes a new technique that may help scientists predict which proteins are prone to misfold and at what point the folding process is likely to break down. The research could support efforts to find the causes for diseases involving amyloids, and it could prove useful for researchers studying proteins involved in even more prevalent diseases like cancer and heart disease. "We know now that most diseases involve proteins going wrong in one of two ways," said lead researcher Cecilia Clementi, assistant professor of chemistry at Rice University. "In the first, proteins don't function correctly because they fold into the wrong shape. This is something we see in sickle-cell anemia, for instance, because of genetic flaws that cause the amino acid sequence to be incorrectly synthesized. "The second way proteins go wrong is by not folding at all, which is what we find in diseases involving amyloids. In these situations, the misfolded proteins assemble together into macroscopic aggregates." Sat, 04 Jun 2005 18:40:23 -0400