Teaching with Schrödinger

Updated: 1-23-22

Protein Structure
Created with: Release 2021-3
Prerequisites: working knowledge of Maestro
Files Supplied: Protein_structure_worksheet
Categories:
high school biology, AP/college general biology

About this Lesson
Proteins are among the most abundant organic molecules in living systems and comein many different shapes and sizes. Many different types of chemical bonds play animportant role in maintaining a protein’s structure. This lesson will focus on the primary,secondary, tertiary and quaternary structure of proteins.
Using Maestro, students will learn how to use the Sequence Viewer to look at individual
amino acid residues, create a peptide sequence, visualize alpha helices and beta
sheets, as well as generate electrostatic potential surfaces of a protein.

Learning Objectives
Understand primary structure of proteins using the Sequence Viewer and the
Build Biopolymer from Sequence panel● Visualize secondary structure motifs such as alpha helices and beta sheets from
the Maestro graphical user interface● Generate electrostatic potential surfaces to view a protein’s overall shape●1
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Standards●

ACS Guidelines○●

ETS Chemistry GRE○●

Biological macromolecules (Section 5.1)
Organic Chemistry – Amino acids, Peptides (3F)

AAMC MCAT○

Structure, function, and reactivity of biologically-relevant molecules (5D)

Assessments
The following types of formative assessments are embedded in this lesson:●●

Assessment of student understanding through discussion of warm-up questions andfilling in any knowledge gaps about structure-based virtual screen steps
Visual assessment of student-generated docking scores from their own set of ligands

Warm-Up Questions: To be done on their own or at the beginning of class
Read the Khan Academy article on Introduction to Proteins and Amino Acids and answer thefollowing questions:
1) What are the 4 main categories of amino acids according to the article?

2) Define what protein denaturation is.

Lesson Outline
1.
2.
3.
4.
5.
6.
7.

What you will need for this lesson - p. 3
Introduction to Protein Structure - p. 5
Primary Structure - p. 8
Secondary Structure - p. 15
Tertiary Structure - p. 19
Quaternary Structure - p. 23
Summary, Additional Resources, and References - p. 24

2
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

1.

What you will need for this lesson
1. Go to the ‘Data’ folder and open yourClass Folder found on the virtual
cluster’s desktop.
2. Right-click on the folder called“Protein_Structure” and copy folder to
Desktop● Here, you will find the lesson
plan, worksheet, and any
additional resources
3. Open Maestro
a. See Starting Maestro if you
need help

Figure 1-1. Open Maestro.
4. Go to File > Change Working
Directory
5. Find your “Protein_Structure” folderthat you duplicated to your Desktop,
and click Choose

Figure 1-2. Change Working Directory option.

3
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

6. Next, go to File > Save Project As
7. Type “Protein_structure_tutorial”
and click Savea. The project will be titledProtein_structure_tutorial.prj

Figure 1-3. Save Project panel.

Figure 1-4. Choose the best mouse option foryour set up.

8. Finally, check your Mouse Actions
a. PC : Edit > Customize Mouse
Actionsb. Mac : Workspace >Customize Mouse Actions
9. Make sure you have the best option
chosen for your set up. This lesson
was written with a three-button mousewith a scroll wheel, meaning the scroll
wheel is a button as well as a wheel. If
you do not have a mouse, choose
Trackpad.
10. If you are on the Teaching with

Schrödinger virtual cluster, open theProtein_Structure.prjzip file in theProtein_Structure folder
11. If you are accessing this lesson fromyour personal computer, download the
project file here

4
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

2.

Introduction to Protein Structure

Let’s start with what most people think of when they think of proteins – food! For
example, eggs are a great source of protein. When we boil eggs, they go irreversibly
from a liquid state to a solid (i.e. hard-boiled). To understand why that happens, wehave to zoom in to the nanometer scale which is the scale at which proteins thrive. And
what we will find is that heating eggs causes them to form solids because of a rather
innocuous protein called ovalbumin pictured in Figure 2.1.

Figure 2.1. Comparing the size of an egg to a protein called ovalbumin.
The cyan ribbons are showing what is known as the backbone of the protein as itloops through space. These ribbons indicate the secondary structure of the protein
while the grey area highlights the electron density surface of the protein, or thethree-dimensional shape. This protein stands at 7.1 nanometers, and when we heat thisprotein up as we cook eggs, these ribbons unfold into long strings.
These long chains of unwound protein are kind of like spaghetti noodles. Haveyou ever cooked spaghetti so much that you accidently boiled off the water and left thecooked spaghetti in the sauce boil? What happens? All the noodles stick together into a
massive clump that is unfortunately inedible. This is what is happening to ovalbumin
when you heat up your eggs every morning, but on the nanometer scale. As theovalbumin proteins in our eggs unwind they begin to interact with other unwound
ovalbumin irreversibly. What are proteins made up of that cause them to behave this5
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

way? Let’s zoom in to the atomic level at a 0.1 nm scale and see what’s going on in
Figure 2.2.

Figure 2.2. Zooming into an amino acid residue in the protein ovalbumin.
Proteins are made up of several main atoms: sulfur, oxygen, nitrogen, carbon,hydrogen, and the occasional phosphorus. And these atoms are arranged into building
blocks called amino acids. In Figure 2.2, we are focusing on part of a protein with anamino acid highlighted within the dotted line box. There is an amino group shown withnitrogen and hydrogen, and then two carbons along the backbone until you get to thenext amino acid which starts at the following blue nitrogen. The center carbon is
attached to other atoms which are indicated here with the green R. This R is meant torepresent one of twenty or more different side chains that a protein can have.
The twenty amino acids found naturally within our cells are the following divided
up based on their chemistry. Hydrophobic amino acids include glycine, alanine, leucine,isoleucine, proline, and valine. The aromatic amino acids include phenylalanine,tryptophan, and tyrosine. Negatively charged amino acids are aspartic acid andglutamic acid. Positively charged amino acids are arginine, histidine, and lysine,
depending upon their chemical environments. Hydroxylic amino acids include serine
and threonine, and sulfur-containing amino acids include cysteine and Methionine.
6
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Finally, the amidic amino acids are asparagine and glutamine. Each of the amino acids
has their own one letter and three letter code associated with it. You can find a table that
illustrates all of the amino acids here.
Proteins are polymers that are made up of long chains of these amino acids.
Amino acids are linked into a long polymer through the formation of amide bonds via
hydrolysis. Let’s take the example in Figure 2.3 of a short polymer made up of leucine,phenylalanine and alanine. Protein chains are built up from the N-Terminus with
Leucine, which has a terminal amino group to the C-terminus, here with Alanine, which
has a terminal carboxyl group. The amino acids in a protein fit together like a puzzle,
except, unlike a typical puzzle which is two dimensions with similar sizes for eachpuzzle piece, the puzzle pieces of a protein are connected by a string (the backbone ofthe protein) and form a three-dimensional shape. Each individual puzzle piece is anamino acid, and the string in this analogy is the backbone of all the amino acids. Not
only is the string mobile, but the amino acid side chains themselves can rotate and fit
together in different ways over time.

Figure 2.3. Amino acids in a protein fit together like a puzzle.

7
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

3.

Primary Structure

3.1

Using the Sequence Viewer

The simplest level of protein structure is the primary structure which is a sequence ofamino acids in a polypeptide chain. The sequence of a protein is determined by the
DNA of the gene that encodes the protein, or a portion of a protein for multi-subunit
proteins. A change in the gene’s DNA sequence may lead to a change in the aminoacid sequence of a protein. A single change (or mutation) of one amino acid in a
protein’s sequence may have drastic effects on a protein’s overall structure andfunction. Let’s use Maestro’s Sequence Viewer to get a sense of the primary structureof the protein 1Y5M_prepared.

1. In the bottom right, click on the➕

2. Click on the Sequence Viewer toturn it on○ The Sequence Viewer is
now visible at the bottomof your Maestro window○ This shows the amino acidsequence of the protein inyour Workspace
Figure 3-1. Turn on the Sequence Viewer.

8
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

3. To see a specific part of thesequence, Left-Click and drag○ That part of the protein will
be highlighted in blue
4. Type Z on your keyboard,○ Your Workspace iszoomed to that part of theproteinFigure 3-2. The part of the sequence isselected in the Workspace.
5. Right-click on the selectedsequence
6. Go to Representation > Ball &Stick○ Your sequence selection is
now shown in Ball & Stickrepresentation

Figure 3-3. Change the representation of
the sequence selection.

9
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 3-4. Highlight the N-terminus.

7. Now select the first 5 residuesof the sequence and represent
them as Ball & Stick○ This first residue is the N
terminus○ The N-terminus is the startof a protein or polypeptide.
The term comes from thefree amine group locatedat the end of a polypeptide.
8. Type Z on your keyboard○ Your Workspace is zoomed
to the selected N-terminus
9. Now select the last 5 residuesof the sequence and represent
them as Ball & Stick○ This last residue is the C
terminus○ The C-terminus is the endof an amino acid chain,terminated by a freecarboxyl group (O-C=O)
10. Type Z on your keyboard○ Your Workspace is zoomed
to the selected C-terminus

Figure 3-5. Highlight the C-terminus.

Learn More: When the protein istranslated from messenger RNA, it iscreated from N-terminus to C-terminus.
The convention for writing peptide
sequences is to write the sequence from
N- to C-terminus.

10
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 3-6.

11. Click on an empty part of theWorkspace○ The selection is cleared
12. Type Z on your keyboard○ Your Workspace is zoomed
to the full structure
13. In the top left of Maestro, under
Quick Select, click P○ The whole protein is
selected in the Workspace
14. In the center of the screen, click
Style○ The Style toolbox opens

11
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

15. Next to Color Atoms, click the
dropdown
16. Choose Element + Custom
Carbons and pick any color○ The carbon atoms will becolored based on the color
you chose○ The sequence viewer color
is updated with this color

Figure 3.7.

3.2

Creating a peptide

A protein is made up of one or more polypeptide chains. Each polypeptide chain is
made up of amino acids linked together in a specific order. A polypeptide chain is like along word that is “spelled out” in amino acid letters. The structure and function of apolypeptide is determined by the chemical properties and order of the amino acids.

12
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Now you will create your own peptide in Maestro using the Build Biopolymer from
Sequence panel.
1. Go to Tasks > Browse > Protein
Preparation and Refinement >Build Biopolymer from
Sequence○ The Build Peptide from theSequence panel opens.

Figure 3-8. Open the Build Peptide fromthe Sequence panel.
2. Under Title, type Peptide
3. Under Sequence, type PEPTIDE
Note: Capital letters must be used in the
Sequence field
4. Under Shape, choose Structure:
Extended
5. Click Build○ A new entry titled Peptide isin the Entry List
Figure 3-9. Build an extended peptide.
13
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

○ The peptide is shown in theWorkspaceNote: Type Z if you cannot see the whole
peptide.
6. Under Title, type Peptide_alpha7. Under Shape, choose Structure:
Alpha Helix
8. Click Build○ A new entry titled
Peptide_alpha is in the
Entry List
○ The peptide is shown in theWorkspace
Figure 3-10. Build an alpha helix peptide.

Activity: Build a peptide out of the lettersin your name. Note that the letters B, J,
O, U, X, and Z are not valid amino acidsin this activity.

Question #1: Build a peptide out of the letters in your name and take a screenshot of
your peptide. Note that the letters B, J, O, U, X, and Z are not valid amino acids in thisactivity. Feel free to use any other letter to replace them.

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The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

4.

Secondary Structure

In proteins, the primary structure will fold into 3D shapes based on the interactions thatthe various amino acids can make with each other. These shapes are known assecondary structures and there are three main types - alpha helix, beta sheet, andloops.

4.1

Visualizing Alpha Helices

Let’s begin by taking a look at the alpha helices in our protein. In an alpha helix, thebackbone of the polymer of amino acids forms a helical shape like an old-school
telephone cord. The carbonyl of one amino acid forms a hydrogen bond with the amidehydrogen of an amino acid that is four places down in the amino acid polymer
sequence. Oftentimes in biology and biochemistry courses, the hydrogen bonds are
credited with dictating these folds. In reality, however, these secondary structureelements are driven to fold by hydrophobic forces that also govern tertiary folding. Let’svisualize an alpha helix in Maestro.

Figure 4-1. The Sequence Viewer iscolored by secondary structure.

1. In the Entry List, include 1Y5M inyour Workspace○ This protein has alreadybeen prepared for you.
Note: To prepare a protein, use theProtein Preparation Workflow which helps
address many of the issues inherent to a
PDB structure, such as missing hydrogenatoms, missing side chains, missing
loops, alternate positions for side chains.
See the lesson on Protein Ligand
Docking for more information.
2. In Quick Select, click P to selectthe whole protein

15
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

○ The whole protein ishighlighted in the Sequence
Viewer
3. Left-click the protein sequence in
the Sequence Viewer, and dragthe mouse over the sequence tohighlight a protein sequence.

16
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

4. Then you can select certain alphahelices and they may look like this.
○ After the portion you wanthighlighted is highlighted
you can click style andchange the color of thehighlighted portion, so thatit stands out from the rest.
Note: Interactions in the bottom rightcorner of the screen must be turned on.

Figure 4-2. Visualizing hydrogen bonds inan alpha helix.

17
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Question #2: In the alpha helix that you are visualizing, how many hydrogen bonds canyou see? (Note that hydrogen bonds are represented by dotted yellow lines). What typeof change do you think the hydrogen bonds are implementing on the structure? Are thehydrogen bonds there for the stabilization of the peptide?

4.2

Visualizing Beta Sheets

Now we will highlight the beta sheets. Beta sheets (also Beta-pleated sheets) are acommon motif of a secondary structure in proteins. Beta sheets consist of beta strands(also B-strand) connected laterally by at least two or three backbone hydrogen bonds,
forming a generally twisted, pleated sheet. In beta-sheets, the backbone of the polymerof amino acids forms an S curve, and the carbonyl carbon of one amino acid forms ahydrogen bond through space with the amide hydrogen of a different amino acid that isfurther down the polymer chain. In molecular modeling, a beta sheet is shown witharrows pointing in the direction where the carbonyl end of the amino acids are pointing.
Let’s visualize a beta sheet in Maestro.
1. Locate a Beta Sheet in a protein
structure that looks similar to
the image on the left.

Figure 4-3.

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The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Question #3: Secondary structures in proteins are all about interactions of the actual
backbone. Go to 3JQO_prepared in your entry list. Take screenshots of an alpha helix
and a beta sheet. List what types of interactions are shown in each.

5.

Tertiary Structure

In this section, we will be able to visualize the tertiary structure of a protein. Tertiary
structure is the arrangement of the secondary structures into a final 3-dimensional
shape. The secondary structure motifs fold into an overall arrangement that gives rise
to a unique protein type with a unique shape and function. The chemical properties ofthe various R-groups or side chains of the amino acids within the protein influencessuch folds. Knowing the tertiary structure of a protein is often crucial to understanding
how it functions and how to target it for drug therapy or other medical uses. Let’s use
Maestro to visualize an overall protein shape by generating an electrostatic potential
surface.

5.1

Visualizing Protein Surfaces
1. To put a surface on a protein,click Style > Surface and it willappear in the workspace○ If this action has been
completed, you will see agrey surface form aroundthe protein

Figure 5-1. Opening the Style panel to add a

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The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Surface.
2. To edit the surface, click the S
button to the right of the entry
name in the Workspace
Navigator. Right click the S andpress Display Options
3. Change the Style to solid andthe Color Scheme toelectrostatic potential

Figure 5-2. Visualizing a protein surface.

20
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 5-3. Changing the surface color
scheme to electrostatic potential.

21
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

5.2

Visualizing Binding Sites
4. The binding sites are the dips andholes in the structure where a
receptor molecule can bind to it.
Analysis:○ Can you see the differencesin the binding sites?
○ Is it easier to understandwhy not every molecule canfit into a certain receptor?
○ And why is shapeimportant?

Figure 5-4. Visualizing the binding pocketof a protein.
Question #3: Electrostatic surface potentials are colored red for negatively charged
residues and blue for positively charged residues, while white/gray represents neutral
residues. Look at the active site region where the ligand is bound. Can you see thedifferences in the binding sites? Is it easier to understand why not every molecule canfit into a certain receptor? And why is shape important?

22
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

6.

Quaternary Structure

Some proteins are made up of more than one amino acid chain, giving them aquaternary structure. These multi-chain proteins are held together with the same forces
as the tertiary structure of individual protein chains (hydrophobic, hydrophilic,
positive/negative charges, etc.). Sometimes the protein chains in a complex are
identical, making it a dimer, or may vary. Some examples of protein complexes withquaternary structure are potassium channels, antibodies, and G-proteins.
In this last section, we will be looking at the protein 3JQO_prepared. It is a 42 chain
structure with sequence from E. coli. Using what we learned from the previous
sections, answer the following question:
Question #4:
Using the Sequence Aligner, list the first 5 amino acid residues in chain A (3JQO_A).
Zoom into these residues in your workspace and take a screenshot.

Question #5:
Find an alpha helix and a beta sheet in this protein complex and take a screenshot of
each.

23
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

7.

Summary, Additional Resources, and References

In this lesson, students learned how to use the Sequence Viewer to look at individual
amino acid residues, create a peptide sequence, visualize alpha helices and beta
sheets, as well as generate electrostatic potential surfaces of a protein. Using Maestro,
students were able to interact with proteins by using the graphical user interface tozoom in/out, translate, and move around various protein structures.
For further information, please see:[1] https://en.wikipedia.org/wiki/Alpha_helix[2] http://proteopedia.org/wiki/index.php/Proteopedia:Table_of_Contents[3] https://www.rcsb.org/search[4] http://proteopedia.org/wiki/index.php/Introduction_to_protein_structure

Entry List - a simplified view of the Project Table that allows you to perform basic
operations such as selection and inclusion
Included - the entry is represented in the Workspace, the circle in the In column is blue
Project Table - displays the contents of a project and is also an interface for performing
operations on selected entries, viewing properties, and organizing structures and data
Scratch Project - a temporary project in which work is not saved, closing a scratch
project removes all current work and begins a new scratch project
Selected - (1) the atoms are chosen in the Workspace. These atoms are referred to as"the selection" or "the atom selection". Workspace operations are performed on theselected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row
for the entry is highlighted. Project operations are performed on all selected entries
Working Directory - the location that files are saved
Workspace - the 3D display area in the center of the main window, where molecular
structures are displayed

24
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Alpha Helices Peptide - The purpose of a peptide is to react with/ perform biological functions
Beta sheets - A secondary structure that can occur in proteins
Monomer - A molecule that binds to other identical molecules to form a polymer
Hydrophobic - an area that repels water, typically made of nonpolar atoms

25
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.