Fold-It!

So, for those of you who don't know, Fold-It is an experimental video game about protein folding. It developed as a collaboration between the University of Washington's departments of Computer Science and Engineering and Biochemistry. Recently, the gamers of Fold-It solved an HIV enzyme riddle in only 3 weeks! If you would like to read about this on Scientific American, click here.

Now, to the game of Fold-It! Honestly, I expected it to be very boring. But I was pleasantly surprised to see the sharp visuals and cool features! The game even had sound effects, and we all know sound effects make everything better. I felt a great sense of accomplishment every time I finished a puzzle, and then I realized I was doing only the simple introductory ones.

So, I started off doing levels 1 and 2. These were a breeze and didn't require much thought. But in order to get to the higher level puzzles, I had to do them because you can only unlock upper levels by completing lower level ones.

Then, I completed level 3-1: Sheets Together.

This puzzle mostly involved hydrogen bonding. It started off with just one hydrogen bond, and ended with five of them. To solve the puzzle, I pressed wiggle for a few seconds, and then I pressed stop. By doing so, the protein's sidechains and backbones were wiggled into place, and hydrogen bonds were formed. Initially, the one hydrogen bond holding the two sheets was very weak. But with the addition of four more hydrogen bonds, the sheets were slightly more stable in their holding together, hence the name "Sheets Together."


Afterwards, I completed level 3-2: Lonely Sheets.

This introduced rubber bands to help solve the puzzle. I noticed there were many empty voids in the beginning. So I put two rubber bands across the greatest voids and pressed wiggle. This helped lessen the voids. However, by doing so I ended up creating some more voids! So I put another rubber band across the protein and pressed wiggle. This helped and at this point, I only needed 16 more points to complete the puzzle. I put another rubber band across the widest space of the protein, and pressed wiggle. After half of a second, I pressed stop. And thus my puzzle was complete! The usage of all of the rubber bands were to bring the sheets together and help them create bonds. The most challenging part of this puzzle was figuring out where to place the rubber bands. And I did mess up a few times. But luckily I discovered the undo feature which helped me fix any errors. In the end, the sheets were brought together and were no longer, "Lonely Sheets."

Next, I completed level 3-3: Sheets and Ladders.

This structure started out looking like a big "S". I decided to follow the same method that I used in the previous puzzle. I immediately placed a rubber band across the protein, and pressed wiggle. This caused the protein to fold up into a globular (my fave word!) shape, and a few hydrogen bonds were created. I noticed one large void towards the bottom, so I placed another rubber band across there and pressed wiggle. And just like that, I had solved the puzzle! I did it in only two moves, so I consider that an accomplishment. This puzzle didn't seem too difficult to me, because it was pretty much just building hydrogen bonds by bringing the protein together.

Next, I completed puzzles 3-4: Lock and Lower (not required) and 3-5: Rebuild (not required). Puzzle 3-4 gave me some trouble at first. I was just playing around with it, and pretty much dug myself a deep hole. At this point, I chose to reset the puzzle and not too long after I solved it. Although 3-5 looks complicated, I was able to solve it in two moves! I just used rubber bands and wiggle to do so.

Last but not least, I completed level 4-1: Hide the Hydrophobic.

For a level 4 puzzle, I was expecting it to be very complicated and difficult. But it was exactly the opposite. There was an orange hydrophobic region and a blue hydrophilic region. First I dragged the orange hydrophobic region towards the center to "hide" it from the exterior. Next, I dragged the blue hydrophilic region towards the outside, so it could be "exposed" to the exterior. The puzzle perfectly fit it's cute name, "Hide the Hydrophobic."

All in all, I actually enjoyed doing the Fold-It puzzles. I learned a little bit about proteins along the way, and I got to have fun playing with the structures. If this sounds interesting to you, I would say give it a try!

Chapter 4 Post

Tay-Sachs Disease


A child with Tay-Sachs disease

Tay-Sachs disease is a genetic disorder caused by the absence of a vital enzyme called hexosaminidase A, abbreviated as Hex-A. Hexosaminidase helps break down gangliosides, a chemical found in nerve tissue. The lack of gangliosides, specifically ganglioside GM2, causes build up in cells. This especially includes nerve cells in the brain.


Tay-Sachs is caused by a defective gene on chromosome 15. Tay-Sachs is a recessive gene, so it can only be developed if both parents carry the gene. If both parents carry the gene, the child has a 25% chance of having Tay-Sachs. If only one parent carries the gene, the child may be a carrier.


Anyone can be a carrier of Tay-Sachs disease, but it is most common in the Ashkenazi Jewish population. There are three forms of Tay-Sachs; classic infantile, juvenile, and late onset. The most common of these is classic infantile, when nerve damage begins when the baby is in the womb.  Symptoms appear when the child is 3-6 months old, and quickly gets worse. In this situation, the child usually dies by age 4-5.


Unfortunately, there is currently no treatment and no way to prevent this deadly disease. However, you can get genetic testing to detect whether you are a carrier for the disorder.

A karyotype of an individual with Tay-Sachs disease

Article link: Tay-Sachs Disease
National Tay-Sachs & Allied Disease's Website: NTSAD.org




Beyond the Signal Sequence: Protein Routing in Health and Disease

So, this article was very long! After spending an hour and not even getting through an eighth of it, I think I will save the full reading for another time.

It all started in 1971 when Gunter Blobel proposed the "signal hypothesis." Blobel speculated there is a fundamental signal that governs protein movement across membranes. Blobel and others consequently revealed other "address tags" that direct proteins to intracellular organelles. These principles are universal, operating similarly in yeast, plant, and animal cells. Blobel's work was recognized in 1999 with a Nobel Prize in "Physiology or Medicine." Recent evidence, based from mutations that result in human disease, led to another conclusion: "the successful intracellular routing of many proteins is also governed by a sensitive quality control (QC) system that recognizes particular structural motifs, then retains and degrades defective molecules". Abnormal proteins are very dangerous to cells because they interfere with normal functions and may result in cell death.

Gunter Blobel

The article continues on to describe protein processing and the role of chaperones, diseases caused by defective routing, diseases caused by conformation errors, and rescue of defective proteins.


Article Link: Beyond the Signal Sequence


Useful Material: Cell Organelles YouTube Video

WARNING: this video is extremely lame! And I doubt the song will become a Top 40's hit, but that's not the point. It explains the major organelles (vacuoles, nucleus, golgi, ER, chloroplasts, etc.) and their functions. I find this kind of similar to the "atom video" we saw in freshman year biology. So if you chose to watch the video, the chorus will probably become stuck in your head. My whole family found this out the hard way. Rhymes always help me retain information better, so hopefully it will help you too!

"Cells, cells, they're made of organelles. Try to pull a fast one, the cytoplasm gels. The nucleus takes over, controlling everything. The party don't stop 'till the membrane blocks the scene."

Chapter 3 Post

Summary of Virtual Lectures:


Proteins


Proteins are defined as polymers found in all cells which play critical roles in nearly all life processes. They account for about 50% of the organic material in a typical animals body.


Proteins have multiple functions. One of these is structural support. They contribute to the stability of a cell. They are also catalytic in nature meaning some proteins act as enzymes. Enzymes are important because they speed up chemical reactions. In addition there is membrane transport. Membrane proteins regulate what comes in and out. Also, proteins contribute to cell motility, hormones, regulation, reception, defense and storage. The point is: they are VERY important to the cell.


There are four progressive levels of protein structure.

• Primary structure is the sequence of amino acids in a protein. The amino acids are connected through peptide bonds. Peptide bonds are formed through dehydration synthesis. Proteins differ in their primary structure. In order to make both the hydrophilic and hydrophobic amino acids happy, proteins are folded. Proteins must be folded based on the linear sequence of amino acids. By doing so, we're burying the ones that are hydrophobic, and exposing the ones that are hydrophilic.
• Secondary structure is when amino acids interact with their neighbors to bend and twist protein chains. The ultimite goal of this is to hide the hydrophobic amino acids. One type of secondary structure is the alpha-helix (α-helix). Hydrogen bonds are what stabilize the twists and turns the protein has. This is where electronegativity (and my favorite Pauling Scale!) comes back in. In the example, the hydrogen has a partial positive charge (a symbol that looks like this δ⁺) and the oxygen has a partial negative charge (δ^-). These opposite charges (remember, opposites attract!!!) in close proximity are what form hydrogen bonds. The other type of secondary structure is the beta-strand (β strand). The beta-strands are zig-zags in flat plane, looking almost like a linear chain. Beta-strands form beta-sheets. Beta-sheets run antiparallel so that hydrogen bonds can be formed by the δ⁺ and δ^- charges. The secondary structure makes the primary structure much more compact. 
• Tertiary structure is the overall conformation or three-dimensional shape of a protein. Proteins can ONLY function in their tertiary structure. In the tertiary structure, the protein ends up taking a globular (I love this word for some reason!) shape, or you can be boring and call it a spherical shape. At the core of our globular structure will be the hydrophobic non-polar amino acids, hiding behind the hydrophilic ones. R-groups, also known as side chains, form ionic bonds and stabilize tertiary structures. There are different interactions that occur, the strongest being disulfide linkages. Disulfide bridges help to stabilize a protein's compact structure. Also, there is denaturation, the loss of protein structure and function. Denaturation can be caused by high heat, a change in pH, or an increase in salt. This is why you can possibly die if you have a very high fever. However, not all hope is lost. It is possible to proteins to renature if the heat, pH, salt gets under control.
• Quaternary structure is two or more proteins joined together into a larger complex protein. Hemoglobin is an example. It contains 4 globin molecules and 4 heme groups.

Nucleic Acids

Nucleic acids are long polymers of nucleotide building blocks. The two classes of nucleic acids are DNA (which stands for deoxyribonucleic acid) and RNA (ribonucleic acid). DNA stores all the information for proper cell function. DNA information also determines the primary structure of proteins. Nucleotides are composed of a five-carbon sugar, nitrogenous base, and three phosphate groups. A difference between DNA and RNA is that DNA has H on its 2' C and RNA has OH on its 2' C.

Then, there are nucleosides. Nucleoside refers to the sugar and nitrogenous base. As you add phosphates, it becomes a nucleoside monophosphate (1 phosphate), a nucleoside diphosphate (2 phosphates), and a nucleoside triphosphate (3 phosphates).

Nucleotides vary in sugar (ribose or deoxyribose) and in nitrogenous base. There are 20 amino acids that are used to make a protein. But only 4 distinct amino acids are used in DNA and RNA. The 4 used in DNA are A, T, C and G. The 4 used in RNA are A, U, C, G. The categories of these are purine (double rings) including A, G and pyrimidine (single ring) including U, T, C.

The reason why DNA has its double helical structure is because of the hydrogen bonds that form between the δ^- oxygen and the δ⁺ hydrogen. DNA and RNA polynucleotide chains are formed by linking the phosphate group of one nucleotide to the sugar of the next one. These are linked together by phosphodiester bonds, covalent bonds specifically found in nucleic acids. DNA runs anti-parallel. One side runs 5' to 3' and the other runs 3' to 5'. Two strands of DNA are joined by hydrogen bonds between the nitrogenous bases following base-pairing rules: A-T and C-G. Adenine and thymine form 2 hydrogen bonds. Cytosine and guanine form 3 hydrogen bonds.

Note: I have not included useful materials in this post because I have done the Fold- It Assignment.

Thalidomide Approved!

This article is about thalidomide, and how it has received approval from the FDA.

Thalidomide was used by pregnant women in the 1950's and early 1960's to help with morning sickness. However, many babies whose mothers took thalidomine were born with horrible birth defects. These include shortened and missing limbs. Since then, thalidomide has had a bad reputation.

New research has been put into thalidomide and it appears that it could help treat people with skin lesions and multiple myeloma. Studies show that thalidomide is effective with slowing the growth of myeloma cells and prevent them from attaching to bone marrow cells.

In addition, thalidomide has shown potential in treating inflammatory diseases, HIV related mouth/throat ulcers, and cancer. More research is needed for approval to help these disorders.

Thalidomide has a few minor side effects that include drowsiness, dizziness and rashes. Researchers are working hard to make thalidomide analogs, drugs which are chemically similar. Hopefully thalidomide can lose it's bad rep and become a beneficial drug.

Chapter 2 Post

I. Summary:

Everything that is currently living or has ever lived is composed of matter. Matter is defined anything that contains mass and occupies space. All matter is composed of atoms. Atoms are the teeny tiniest units of atoms that form all chemical substances.

Each specific atom type is called an element. An element is a pure substance of only one kind of atom. Three subatomic particles make up atoms. They are protons, neutrons and electrons. Protons have a positive charge and are found in the nucleus. Neutrons have a neutral (no) charge and are also found in the nucleus. Electrons have a negative charge and are found in orbitals, which I discuss below.

Electrons are extremely fast, so it's hard to predict the location of a given electron. But we can describe where there is a high probability of finding one, using regions called orbitals. You can think of it as a cloud. Spherical orbitals are called s orbitals. P orbitals have a propeller or dumbell shape. Slightly confused? I was at first too. But looking through the pictures in the book helps.

Orbitals occupy energy shells, aka energy levels. The inner energy shell can hold only 2 electrons within an s orbital. The second shell has 1 s orbital and 3 p orbitals. Each of these orbitals holds a pair of electrons, so the second shell holds 8 total. Electrons tend to fill the s orbitals first, and then the p orbitals one electron at a time.

The majority of atoms have outer shells that aren't completely filled with electrons. Those electrons in the outer shell are called valence electrons. Valence electrons are a crucial part of bonding, which is coming up soon.

Each element has a unique atomic number.
Atomic number = Number of protons = Number of electrons

Now let's talk about atomic mass. It's measured in daltons, aka atomic mass units. One dalton = 1/12 the mass of a carbon atom, so carbon has a mass of 12 daltons. Then there are moles. A mole of any substance has the same number of particles as there are atoms in carbon. To put it simply, a mole of all substances have the same number of atoms. This number, 6.022 x 10^23, is Avogadro's number.

An element can have different numbers of neutrons, called isotopes. Isotopes don't change the charge of the atom, but they change the mass. There are also unstable isotopes called radioisotopes.

The next major part of the chapter talks about bonds. There are 3 major types; covalent (which can be further subdivided into polar and nonpolar), hydrogen and ionic. Each type of bond has specific characteristics that I found quite simple.

Then there's free radicals. A free radical is a molecule that has an atom with a single, unpaired electron in its outer shell. Free radicals are very lonely so they try to steal electrons from another molecule's atom. This pretty much sets off a chain reaction of free (lonely) radicals.

Let's move on to chemical reactions (fun!). These happen when substances change into other substances. They require an energy source and reactions in living organisms may need a catalyst (like enzymes).

Next the book talks all about water. A solution is composed of a solvent and a solute. In aqueous solutions water is the solvent. Hydrophillic means water loving and hydrophobic means water fearing. There's also amphipathic molecules that have both polar and non polar regions. Solute concentration is how much solute there is in a solution. It's usually in g/L. Molarity is the number of moles of a solute dissolved in a liter of water.

II. Useful Materials

I found this video pretty helpful with mole conversions, something described in the chapter. The man in the video works it out very simply, step by step.

So, I know what you're thinking. This guy is slightly crazy. But, he does explain and prove the point well about how hydrophillic and hydrophobic bonds work.

This article from PubMed talks about interaction energies between different ions. Different model complexes are tested with different ions. Also mentioned is interaction energies underlying the theoretically predicted metal-ion selectivity and the effect of geometry optimization on these values. This relates to our chapter because it highlight intricate ionic bonds and how they interact with free energies.

New Radioisotope May Enhance Cancer Therapy!

This article focuses on the radiopharmaceutical ¹⁶¹Tb, an isotope of terbium. The Institut Laue-Langevin (ILL) has recently produced samples of ¹⁶¹Tb that could potentially help diagnose and treat cancer.

Radiopharmaceuticals are radioactive isotopes which are attached to a bioconjugate that is selectively delived to cancer cells.

Current radiopharmaceuticals such as ¹⁷⁷Lu (an isotope of lutetium) are already very successful in fighting certain types of cancer, but those isotopes are not ideal for all therapeutic uses. They could cause added damage to healthy tissue or require patient isolation during treatment.

¹⁶¹Tb is similar to ¹⁷⁷Lu, but it emits more low energy electrons. This means it would be more efficient for treating smaller tumors. ¹⁷⁷Lu is already in use in several countries that include Australia and Brazil.

¹⁶¹Tb also has advantageous decay properties for usage in cancer treatment. For example, it has a half life of 6.9 days, long enough to transport to hospitals but short enough not to pose any long term issues of waste handling after excretion.

¹⁶¹Tb seems to have a lot of potential. If financial backing is found it may be able to be routinely produced by 2013.

Article Link: New Radioisotope Will Improve Cancer Therapy

-Em Fu The Science Guru