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Molecular Basis of Sickle Cell Disease

Author(s): Didem Vardar-Ulu

Boston University, Chemistry Department

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This multi part case on hemoglobin structure as it relates to oxygen binding and sickle cell disease focuses on utilizing bioinformatics and molecular visualization tools to learn about the sickle cell disease, its cause, symptoms and possible cures.


Molecular Basis of Sickle Cell Disease

Overview: This case is an adaptation of the Nicholas's story that discusses Nicholas' experiences with sickle cell disease.  Background materials about the original case are included in the pre-class worksheet along with additional information and exercises. The in-class section is divided into three parts that contain the core of the molecular visualization exercises.  The first part focuses on understanding oxyen binding through using the RCSB Protein Data Bank resources as well as the Online Macromolecular Museum exhibit.  Second part focuses on developing a molecular understanding of sickle cell disease using the the Online Macromolecular Museum exhibit.  The last part 's designed to have students discuss in molecular terms the cause of Nicholas's pain and propose  interventions that would prevent pain crises.  

Learning Objectives: This adaptation was developed for an upper level one semester introductory biochemistry course without a laboratory taken primarily by premed students.  As a chemistry cause the emphasis is on the molecular details and the students are expected to be familiar with basic protein structure and noncovalent interactions to best benefit from the activity.    By the end of the case, students should be able to:

  • retrieve protein sequences from public repositories
  • obtain basic information about the protein sequences using open license software
  • align and compare protein sequences using open license software
  • predict secondary structure of proteins based on sequence using open license software
  • use RCSB Protein Data Bank to retrieve structural information about proteins whose 3D structure is deposited in the databank
  • explore molecular interactions by visualizing available 3D protein structures with freely available online tools
  • explain the molecular basis of oxygen binding to hemoglobin and the structural changes associated with oxygen binding
  • explain the molecular basis of sickle cell disease and the structural changes associated with the single point mutation underlying the sickle cell disease

Molecules explored: The primary molecule studied in this case is hemoglobin, including structures of native, mutant, and variant proteins; and complexes with drugs and various small molecular ligands.  Students are also asked to look into myoglobin during their pre-class work as a preparation for the case.

Implementation: The case is designed to be delivered in an hybrid approach with pre- and post- sections implemented using a flipped approach in-class section carried out in person.  However, each section can be delivered with the other modality as well.


This adaptation to the original case was made to:

1.    Directly complement the content covered in the course curriculum that uses the text book:

A Short Course by Tymoczko, Berg, and Stryer

2.    Allow a smaller facilitator to student ratio for the in-class activity by offering the in-class session on two consecutive time blocks each for half the student population. With this arrangement each session had 56 students (7 round tables of 8 students), guided by one instructor, one teaching assistant (graduate student), and one undergraduate assistant.  Students were given a week prior to their arranged in-class activity time to complete the pre-work and four days after the completion of the in-class activity to complete and submit their post0class work.  The in-class portion of the activity was carried out during the scheduled “exam block” time slot for the course that was 2 hr. long.  The in-class test was delivered via TopHat test during the last 15 minutes of this time block.

3.    To ensure that all students came into the “in-class” portion of the activity with similar content and skill competencies (development of pre-class worksheet)

4.    To ensure that the in-class time (in-class worksheet) focused on competency areas where students were least familiar with (i.e. molecular literacy – how to interpret structural information presented through figures to explain functional outcomes)

5.    To create modular assessments that evaluated different levels of acquired competencies (in-class test: to evaluate immediate basic and intended direct outcomes as well as post-class assessment to evaluate the student’s ability to apply what they have practiced in class to a related but new problem)

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