Protein Pirouettes: Part 2

Amyloid

Welcome to our Protein Pirouettes series! This series is designed to teach you about the wonderful world of proteins, so that you too can learn to dance like a protein. If you haven’t read our introduction- check out the first part of the series here. You can also watch this great video here– for expert level dancing on the smallest possible scale. For more information about the author, check out our about us page.

Hello readers! Cooper here! Welcome back to our Protein Pirouettes series. In the last article, I talked a lot about where proteins come from, why they need to fold, and touched on the elaborate dance of protein folding that proteins must perform to function. In this article, we’ll dive deeper into this process, and explore what happens when it goes horribly wrong. 

When you’re stuck in a rut, just keep dancing.

As proteins twist and turn, they take on different shapes that we call conformations. In search of a functional, highly organized, low entropy shape, proteins sometimes get stuck into non-native conformations (intermediately folded states, or simply called intermediates).2These chaotic, entropy laden states are intermediates on the pathway towards fulfillment of the protein’s purpose. Oh, woe is the protein! But do the little dancers give up? Of course not—they do what they always do. They dance

Protein Chain Diagram
Simplified protein folding funnel, showing a handsomely drawn protein perform the Cha Cha slide. Two hops this time!

 

The protein vibrates with wanton abandon, strands of amino acids bumping into each another recklessly and randomly, trying out new moves. It doesn’t give up. Eventually, something just seems to feel right, the protein settles into its groove and becomes more stable, escaping the rut and dancing towards its goal. When faced with a hurdle in life, consider meeting the challenge like a protein: just keep dancing.

Friends don’t let friends dance alone.

Remember the chaperones at your high school prom? Proteins don’t always get to dance without chaperones either. Sometimes, to dance their way to the next conformation, proteins enlist the help of a chaperone.3Chaperones are protein themselves, and when they see a fellow protein dancing, they get up and dance along with them! Cells are like busy night clubs, and it’s hard to dance when there are innumerable other proteins dancing all around you! Just like our high school prom chaperones, protein chaperones facilitate the party so that nothing too-crazy happens. After all, sometimes dancing doesn’t turn out like it should. 

Amyloid
If you’re an amyloid, you’re going to have a bad time.

Go home amyloid, you’re drunk.

Without the safe watch of a chaperone, proteins may accidentally take on a misfolded conformation that is particularly terrible. These misfolded proteins are like that guy at prom that drinks a little bittoo much of the booze he stole from his parents, and ends up vomiting all over the hardwood dance floor of the gym. Don’t be that guy. Proteins don’t want to be that guy either, and, in the world of proteins, that guy’s name is amyloid.3Amyloids form when misfolded proteins get squished together, and they’re dangerous to your health. For example, plaques of amyloid beta proteins are implicated in the development of Alzheimer’s disease.6So, take a tip from proteins: dance responsibly. 

—Cooper

Notes

  1. Video clip of a protein folding simulation.1
  2. Protein folding funnel drawn in Microsoft Paint. The width of the funnel represent entropy, with decreasing entropy as the funnel narrows. The height of the funnel represents Gibbs free energy, with energy decreasing from top to bottom.2
  3. Adapted, surface structure of a 42-residue beta-amyloid fibril (2MXU) visualized in NGL.4-5

References

  1. Theoretical and Computational Biophysics Group at the NIH Center for Macromolecular Modeling and Bioinformatics. Folding of a Three-helix Bundle Protein. Online video clip. YouTube. 2013. Retrieved from https://www.youtube.com/watch?v=XsQgjxMDjNw.
  2. Wolynes PG, Onuchic JN, Thirumalai D. Navigating the Folding Routes. Science. 1995;267(5204):1619.
  3. Dwevedi A. Protein Folding: Examining the Challenges from Synthesis to Folded Form. SpringerBriefs in Biochemistry and Molecular Biology. 2015. ISBN 978-3-319-12592-3. 
  4. AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlić and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ’16): 185-186, 2016. doi:10.1145/2945292.2945324.
  5. AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402.
  6. Aisen PS, Cummings J, Jack Jr. CR, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther. 2017;9:60. doi:10.1186/s13195-017-0283-5.

Protein Pirouettes: Part 1

Ezetimibe

How to Dance Like a Protein: Part 1

Ezetimibe
Pirouettes performed by the target protein of the drug ezetimibe, a medication used to lower cholesterol (a).

Proteins—the practically invisible, molecular dancers that serve as the faithful building blocks of me and you. Yes, it is true that even dancers are made of dancers, and proteins perform some of the most amazing dancing of all by way of folding. Protein folding is actually a lot like belly dancing, with all of its vibrations and shimmying.

Now, I am not—by any leap of the imagination—a dancer, but I do happen to know a lot about nature’s smallest dancers of all. Perhaps you can find some inspiration in learning about our nanoscopic friends, and learn about the science of protein folding along the way!

Butterfly Protein
The humble butterfly protein. Or two chicken legs pressed together? Choose your own adventure (b).

A reason to dance. What, you think that the protein above woke up looking that beautiful? To understand how and why a protein folds, it’s important to remind ourselves of how they come to exist in the first place—the central dogma of molecular biology. DNA is transcribed into mRNA, and mRNA is translated in proteins. That probably sounds like an awful lot of alphabet soup, but let’s simplify things with an analogy: your cell is a small company called Cell Incorporated®. Every company needs a CEO to boss everybody around, and that’s “DNA” (deoxyribonucleic acid), whose office is located in the center (nucleus) of Cell Inc.®. However, even a visionary leader is powerless if they cannot communicate that vision, so they employ messengers called “mRNA” (messenger ribonucleic acid). Now, the company needs to produce something to make a profit, and that product is called “proteins.” Ergo, the central dogma of molecular biology: DNA -> mRNA -> proteins.

To make their product, Cell Inc.® needs raw materials—these are chemicals called amino acids, the steel from which proteins are made. As a protein is being constructed (or translated from the “language” of nucleic acids to amino acids), it is formed piece by piece in a long chain. Imagine that every component that makes up a cell phone was attached to one another by a tiny string; if you laid out that string, it would look nothing like a cell phone (let alone work like one), and the same is true for proteins. Unfortunately for them, cells don’t have the benefit of assembly lines and blue collar workers; therefore, the product must put itself together.

Understand the immense difficulty of this task for a moment: Cell Inc.® needs to make a product out of steel blocks connected by string that, due to the unique properties of each block, will self-assemble into something useful, something beautiful (cell phones are beautiful, okay?).

Wow.

Fortunately for them, however, cells possess the most powerful allies in the entire universe: the laws of physics (c). And it is these laws that govern what is possible, what is probable, and what isn’t. Using physics, Cell Inc.® came up with a solution to make its products self-assemble—to make the pieces of the protein fold nicely together: they dance.

Dancing with purpose. There, I said it: protein folding is dancing. Proteins jiggle, wiggle, twist, and turn, always moving, vibrating, and colliding with themselves and anything else around. Although the motions may be random, the dance itself is done with an immense sense of purpose, guided by the very nature of the protein itself. From chaos and entropy, proteins allow their amino acid bodies to guide their movements towards the native structure, the final, functional form of proteins that we’re familiar with (see the image above). From the very moment that a protein is born, it begins to fold—dancing, you might say, is an integral part of the nature of what it means to be a protein.

There’s an important life lesson to be learned from the humble protein, here. We should allow our natural talents and capabilities to guide our decisions, rather than force upon ourselves choices that deviate from the desires of our hearts. In the early moments of a protein’s birth, it seems impossible to foresee anything of worth or interest arising from a tangled mess of amino acids slapped together, moving erratically in the dark loneliness of a cell. However, perhaps if we live our lives like a protein—following our hearts, listening to our bodies, and maybe even a little dancing—we can find fulfillment, and become the best, most beautiful version of ourselves that we can be.

You do you, aquaporin. You do you (d).

To learn more about proteins, check out my second article here. I’ll be exploring protein folding in greater detail, and discuss how even one false move on the dance floor can transform an otherwise contributing member of cellular society into a murderer.

—Cooper

TL;DR:

  • Proteins are made up of amino acids
  • Central dogma of molecular biology: DNA -> mRNA -> proteins
  • During and after translation, proteins must fold to become functional
  • Protein folding happens as a consequence of the protein’s inherent chemical structure

Notes

(a) Adapted, surface structure of human NPC1L1 (3QNT) visualized in NGL. (1-2)

(b) Adapted, surface structure of human DNA topoisomerase IIa ATPase/ADP (1ZXN) visualized in NGL. (1-2)

(c) This is ultimately where biochemistry comes from; biochemistry is the study of biological chemicals, chemistry is the study of chemicals and how they interact, and those interactions are governed by the law of physics. Biochemistry is basically biological chemical physics. The laws of physics, as they apply to biological chemicals (biochemistry), govern the movements and interactions of proteins (which are also biological chemicals, albeit bigger ones)—just as they govern the movements and interactions of us.

(d) Adapted, surface structure of bioassembled human aquaporin (4CSK) visualized in NGL. (1-2)

References

(1) AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlić and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ’16): 185-186, 2016. doi:10.1145/2945292.2945324.

(2) AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402.

Part 2 coming soon!

Story of Us

Read the Story of Us

We are an interdisciplinary team made up of pharmacists, bellydancers, social workers, artists, healthcare professionals, and many more. Learn more about our team and the story of us below:

Catlina’s Story:

Catlina is a pharmacy resident with a passion for mental health pharmacy and a set of feet that won’t stop dancing. She graduated with a Bachelors degree from Texas A&M University. There she began her career as a semi-professional belly dancer, making just enough money for some extra glitter. (Can you really ever have enough glitter?) While there she also volunteered on a crisis helpline, and wanted to learn more about mental health.

This lead her to pharmacy school, and a burning desire to know if dance could help those with mental illnesses.  She recently graduated from the University of Texas at Austin College of Pharmacy with her Doctor of Pharmacy degree, and would not have been able to make it through without dancing. She hopes her experience and credentials will provide a unique experience, that proves pharmacists truly do make the best bellydancers, and vice versa. This blog is her way of exploring the connection between dance and medicine.

Rose’s Story:

Rose has always loved art and science. As a child, she frequently wrote poems and flipped through horse care books, and her interests matured as she delved into studies of literature and chemistry in high school, and technical writing and, well, ALL types of science in college. For years, she worked at various small and large animal facilities, pursuing her interest in health. On the side, she would belly dance. Art and science were always a part of her world.

The two worlds finally meshed for her shortly after earning her Bachelor of Science when her mental and physical health struck their lowest point. This forced her to rehabilitate herself via biomedical and alternative treatments. She learned that life and health required a balance between the structured, tested methods of Western medicine and the mysterious artistry of nature and creativity. Now, her heart has guided her toward wanting to help other people find that balance.

Cooper’s Story:

Cooper is a stalwartly optimistic chemist that believes in offering over-the-counter compassion. He also believes in mindful medication management, high doses of humor, and empowering patients to steer their destiny. His hobbies include taking long walks around hospital courtyards, drinking cafeteria coffee (500 mL PO TID AC + HS), and filling the spacious pockets of his white coat with mostly useless things. In addition to these activities becoming of a fine gentleman, he also likes to read books in the breakroom and contemplate philosophy.

Sun’s Story:

Sun is a Licensed Marriage and Family Therapy Associate (LMFT-A) who lives in Texas with her 14-year-old dog. Prior to graduation, she spent her time working with university-level students struggling with various concerns that often directly impacted their academic standing. Whether she’s working with clients or students, Sun believes in collaborative work.

She firmly believes that every client is the expert on their own life, and utilizes that information to promote teamwork and positivity during session. When she isn’t working, Sun enjoys focusing her free time on different forms of self-care. This includes hanging out with friends, wood-burning, PC gaming, and getting lost in good music (to name a few).