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3.) Protein Story Phase: Antibodies

Climbing the Mountain

Antibodies play a critical role in our adaptive immune system, identifying and neutralizing pathogens such as the novel coronavirus of the 2020 pandemic.

The resources below will introduce the basics of antibody structure and function. You will then choose a specific protein story related to antibodies that you want to model. You will read a scientific research article, find an antibody protein structure file, and design a 3D printed physical model of an antibody protein.

Note: If you skipped the Training Phase and need to review basic protein structure-function concepts, visit the Training Phase Protein Structure Resources.

Recommended Models for the Antibody Protein Story Phase

The MAPS program revolves around using physical models as teaching tools. So if at all possible, we encourage you to use the recommended models below for the antibody protein story phase.

All recommended models are available to borrow free of charge through the MSOE Lending Library, or are available for purchase through 3D Molecular Designs. Use the discount code below to receive a 10% MAPS discount on your 3D Molecular Designs purchases.

1. Introduction to Antibodies

In this section, we will explore the basic structure and functions of antibodies, including why we need them and how they help fight off pathogens as part of our adaptive immune system.

An Introduction to Antibodies
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Before we model parts of an antibody, you should understand the BIG picture of what antibodies are, and what role they play in our immune system. The video below will introduce this antibody MAPS module and why antibodies are an interesting protein to study.

An Introduction to Antibody MAPS Module

The next video provides a broad overview of our adaptive immune system, and the crucial role antibody proteins play in protecting us from infections. But beware, this video tries to explain the role of antibodies in fighting infections, in the context of all the different kinds of cells that work together to make up our immune system. In other words, this video presents the main players in our Cellular Immune System, as opposed to our Humoral Immune System, that only involves B-cells….that produce antibodies. So,…. although this is great information if you are studying the Immune System, don’t let it confuse you if you want to focus on the less complicated role of antibodies.

The Immune System Explained

Important Discoveries in Antibody Research
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The Adaptive Immune System is such an important part of modern medicine, that there have been multiple Nobel Prizes awarded in this area of research. Explore the Nobel Prize website link below to learn about some of these amazing discoveries, including three specific awards related directly to antibodies.

Nobel Prizes and the Immune System

The first Atomic-Resolution Structure of an Antibody was determined in 1973 and published by Pljak, Amzel, Avey, Chen, Phizackerley and Saul. Explore the PDF link below to see this early and groundbreaking article.

Pay special attention to the meticulously constructed models and figures shown throughout the paper. . . created well before easy-to-access molecular visualization programs like Jmol!

Three-Dimensional Structure of the Fab' Fragment of a Human Immunoglobulin at 2.8-A Resolution. POLJAK, L. M. AMIZEL, H. P. AVEY*, B. L. CHEN, R. P. PHIZACKERLEY, AND F. SAUL, Proc. Nat. Acad. Sci. USA Vol. 70, No. 12, Part I, pp. 3305-3310, Dec 1973




2. Antibody Structure

In this section we are going to explore the structure of an antibody. This key protein is very modular, being comprised of twelve near identical Immunoglobulin Folds.

The Modular Nature of Antibodies
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In the video below, Dr. Tim Herman discusses the overall modular shape of antibodies and the structure of immunoglobulin folds.

The Modular Nature of Antibody Proteins

Digital Activity - Building an Antibody

The activity linked to below will let you build your own digital antibody from individual immunoglobulin folds. Having a strong grasp of the overall shape and structure of antibodies, and their modular nature, will prepare you for modeling more nuanced details of antibodies later in the module.

Antigens and Antigen Binding
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In the video below, Dr. Tim Herman discusses antigens and antigen binding to antibody proteins.

Antigen and Antigen Binding

Challenge 1: Building Your Own Antibody
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You have arrived at the first major modeling activity of the antibody module! In this modeling challenge, you will construct a physical, schematic model of an antibody using the 3DMD Antibody Student Pack or crafting materials of your choosing.

Modeling a Schematic Antibody

Your antibody model should highlighting the following features:

  1. Four Chains, two Heavy Chains and two Light Chains
  2. The N-terminal and C-terminal ends of each protein chain
  3. The Antigen Binding sites
  4. Each Chain is composed of immunoglobulin folds
  5. Each Chain is covalently linked to another Chain via disulfide bonds

When you are finished, take a photo of your model and share it with other MAPS Teams on the MAPS Discussion Boards.

A 3D Review of Antibody Structure

Now that you are familiar with basic antibody structure and have modeled a schematic antibody, use the link below to explore an antibody in full interactive 3D. This web page uses Jmol, the molecular visualization program you will later be using to create your own physical 3D printed antibody model.

Antibody Structure Jmol Exploration




3. Antibody Diversity

Antibodies play a key role in our adaptive immune system, binding to foreign objects such as the surface proteins on viruses or bacteria and marking them for destruction. The more pathogens our immune system is exposed to, the more diverse the collection of antibodies we will produce, each able to bind to a single specific pathogen fragment.

In this section of the module, we will explore how the antibody gene can produce such diversity.

Challenge 2: Calculating Antibody Diversity
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Every antibody has two antigen-binding domains (Fab), each comprised of one light chain and a portion of one heavy chain. These Fab domains can bind to pathogens, marking them as a foreign object that should be destroyed. Any fragment of a foreign object that an antibody can bind to is called an antigen.

Our bodies produce around one hundred million different antibody structures, each with slightly different Fab domains capable of binding to a unique antigen. But how is this level of diversity possible? How can we fit the genetic instructions for such a large variety of antibody structures into the 3.2 billion basepairs of DNA in the human genome?

Calculating Antibody Diversity



CHALLENGE #2: Calculate the number of base pairs of DNA that would be required to encode 100 million different antibodies.

Start your calculation with the average number of amino acids in an immunoglobulin fold (118 aa). Don’t worry about the (i) number of amino acids in the “linker” regions that join each immunoglobulin fold together, or (ii) the fact that eukaryotic genes are composed of exons and introns.

Once you have calculated this number, discuss your answer. Is your answer reasonable? When ready, move on to the video below to continue to the discussion.

Shuffling the Antibody Gene

The V, D and J Regions
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Antibody diversity allows our body to defend against a huge variety of pathogens. This diversity is the direct result of the unique shuffling of the antibody gene in each antibody producing B-cell. The video below summarizes this reshuffling, with emphasis put on the V, D and J regions of the antibody gene.

Shuffling the Antibody Gene

Digital Activity - Shuffling an Antibody Gene

The activity linked to below will let you shuffle your own digital antibody gene, and explore how this random reshuffling results in a variety of antibodies that can each bind to a different antigen.




4. The Immunoglobulin Fold (IgG)

In this section, we will explore the modular immunoglobulin fold in more detail and create a physical model of a single IgG fold.

Challenge 3: Building Your Own IgG Fold
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Building an Immunoglobulin Fold

Using a 118 cm long mini-toober (from the 3DMD Antibody Student Modeling Pack), or any other flexible material (wire), create a physical model of an immunoglobulin fold. The model should accurately represent the path of the protein’s backbone in 3D space. The model can be based on the structure of Chain A described by 7kkj.pdb.

Before you begin to fold your model, mark on your mini-toober the position of the two cysteine amino acids that will form the covalent disulfide bond that stabilizes immunoglobulin fold.

Note that at this scale, you will not be able to represent the zig-zag shape of each strand of beta sheet. But your model should show the 4-stranded beta sheet and the 5-stranded beta sheet that makes up this fold.

Your final model should display the following features:

  1. The correct path of the protein’s backbone in 3D space.
  2. The two beta-sheets,… one with 4 strands and one with 5-strands.
  3. The disulfide bond connecting the two sheets
  4. The N-terminal end of your model
  5. CDRs 1, 2 and 3 (CDR is the abbreviation for Complementarity Determining Regions)
  6. EXTRA CREDIT: For the over-achievers among you, use Jmol to carefully examine the structure described by 7kkj.pdb … and find:
    • An example of a salt bridge (an electrostatic interaction between an acid sidechain and a basic sidechain) that stabilizes this fold. Represent this salt bridge in some way on our model
    • A pair of buried hydrophobic sidechains that stabilize the structure between the two beta sheets. Represent these hydrophobic sidechain in some way on your model

When you are finished, take a photo of your model and share it with other MAPS Teams on the MAPS Discussion Boards.

A Helpful Folding Guide

Folding an accurate model of an immunoglobulin fold is quite challenging, as the path of the protein backbone jumps back and forth between the top and bottom beta sheets. The link below can act as a helpful folding guide.

Modeling the IgG Fold Jmol Exploration

A Detailed Paper Model of an Antibody
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In this video, Tim Herman introduces another antibody modeling activity in which printed paper can be used to create a detailed twelve-IgG-fold antibody model. PDF documents of all of the paper printouts for the model can be found at http://pdb101.rcsb.org/learn/paper-models/antibody

Building a Detailed Paper Model of an Antibody




5. Defining Your Antibody Protein Story

Now that you are armed with an extensive understanding of what antibodies do and how their structure is important to their function, it is time to decide what specific antibody story you would like to explore.

The expandable content below will give you some suggested topics you may choose to focus on, a recommended antibody research paper to read, and link to a collection of antibody structure files you may choose to use when designing your 3D printed protein model.

The AeroNab Story
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At this point you are ready to decide what antibody story you would like to explore further. There are many amazing molecular stories related to antibodies, any of which would make an excellent MAPS project and lend themselves to a useful 3D printed physical model.

In the video below, Dr. Tim Herman introduces one potential topic, called the "AeroNab" story.

The AeroNab Story

Additional Resources related to the AeroNab Story

Writing an Abstract and Finding a Structure
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Your MAPS Team will want to have a clear idea of what your antibody story is before you start your model design. And one of the best ways to define your protein story is to write a scientific abstract.

Abstracts are, by definition, short. You might want to start with one sentence for each of the sections listed below, and then add additional sentences as needed.

  • Introduction: What is the overall relevance of your protein of interest?
  • Question: What is the particular story of your protein that your team will model?
  • Findings: What answers to your question were you able to determine through your modeling project? Be specific as to what structural elements your team has modeled and how they are relevant to your story.
  • Conclusion: How do your findings relate to the big picture? What important questions related to your protein story are still being actively researched?

Click here to see a sample abstract

Once you have defined the antibody protein story you want to tell, you will need to find a protein structure file that you can work with in Jmol to design your 3D printed antibody model.

Designing and building your own physical antibody model will give you great insight into specific structures that are important to the antibody protein story you have chosen to focus on. Even if you don't have your design 3D printed, studying the 3D design in specialized computer software is still helpful.

Below are a few additional links that may help you in your antibody structure search.

Designing Your Antibody Model with Jmol
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What Does it Mean to "Design" a Protein Model?

Tim Herman, PhD Explains How to Approach Your Model Design in Jmol

"Designing" a protein model means you explore a protein structure in Jmol, and then simplify the way the protein is visually displayed to make the key features of the protein that help communicate your molecular story more obvious.

This can mean hiding some atoms that are not important for your protein story, changing the display format of certain parts of your protein structure or changing colors to best highlight the most important parts of the protein structures. In the next section, you will learn the Jmol commands needed to accomplish this.

How to Approach Your Model Design

Tim Herman, PhD Explains How to Approach Your Model Design in Jmol

All 3D printed protein models made in the MAPS program are designed using the program Jmol. You start with a protein structure file (.PDB file), which contains the 3D locations of all of the atoms that make up the protein. Using the Jmol commands you will learn below, you can then edit the way the protein is displayed, hiding some atoms, changing display formats and customizing colors. When happy with your design, you can export your protein model from Jmol in file formats suitable for 3D printing.

We have created a detailed Jmol Training Guide that will cover everything you need to know to design and build your model. The Jmol Training Guide is broken down into four main sections, which we strongly recommend you explore in order until you are comfortable with Jmol and designing protein models for 3D printing.



Moving to the Next Phase

Once your team has finished the protein story phase, move on the Capstone Experience, where you will learn how to present your project using your 3D printed model and a variety of complimentary digital and print media.