Course: BIOEN 457/599 Advanced Molecular Engineering – Recognition and Design in Molecular Medicine

Credits: 4

Coordinator: Patrick Stayton

Course Description:  Engineers have traditionally played a major role in developing macroscopic   medical technologies such as medical devices and instrumentation. There are also many important new opportunities for engineers to apply their design and analytical skills toward more molecular medical technologies. These opportunities are being created by fundamental advances in our understanding of how biomolecules control healthy physiology, how cells communicate, how the body protects itself against the initiation of cancer, etc. Advanced Molecular Engineering will introduce engineering students to the quantitative aspects of biomolecular recognition through the use of design-­‐oriented case studies of recent molecular medicine advances. After an introduction to fundamental molecular recognition energetics in the context of biomolecular structure, the course will progress from design strategies for molecular therapeutics up through the design of cellular therapeutics.

Prerequisites: General Biology, General Chemistry

Goals: Introduce engineering students to how biomolecular structure and recognition are tied to thermodynamics and reaction kinetics; apply these fundamental structure/energetic principles to the design of biotherapeutics and molecular materials; familiarize engineering students with cutting-­‐edge molecular medicine problems and provide rationale for bringing engineering analysis and design tools into the medical field.


  1. Define thermodynamic principles in context of biomolecular recognition and stability
  2. Define kinetic theory and reaction kinetics in context of biomolecular recognition and stability
  3. Define how non-­‐covalent bonding energetics relate to biomolecular recognition and stability d. Apply biomolecular energetics to biotherapeutic design from a modeling and computational standpoint
  4. Apply combinatorial and directed evolution approaches to biotherapeutic design
  5. g. Define molecular design strategies for modifying cells to develop cellular therapeutics


  1. Mid-­‐Term Examination: 33&1/3%
  2. Final Cumulative Examination: 33&1/3%
  3. Short Literature Reviews: 33&1/3%


In addition to these components, 599 students will submit a technology concept paper that incorporates molecular design and engineering.

Module Lecture Case Study
1 Molecular Recognition Fundamentals: thermodynamics of biomolecular interactions, non-­‐covalent forces underlying bioenergetics: hydrogen bonding, van der Waals, hydrophobic effect, water in context of molecular recognition, biomolecular stability Protein StabilityAntibody-­‐Antigen Energetics
2 Molecular Recognition Fundamentals: kinetic theory, reaction kinetics, enzyme energetics Catalytic Antibodies
3 Rational Molecular Design: molecular modeling, computational approaches to predicting molecular recognition energetics PeptidoMimetic therapeutics
4 Directed Evolution for Molecular Design: random mutagenesis approaches and techniques, phage display and selection techniques, combinatorial approaches and techniques Antibody Engineering, enzyme engineering, phage display
5 Cellular Warfare: receptor-­‐mediated recognition in immune system surveillance, macrophage-­‐B-­‐Cell collaboration, T-­‐Cell and natural killer cell function, vaccines Engineered T-­‐Cell Therapeutics, Vaccines


Short Literature Reviews

Each student is required to write 4 ONE PAGE reviews of primary literature papers selected from the case study areas 1-4. These reviews should capsulize the key findings of the paper under the following subheadings and with the following guidelines:

  1.  Introduction -­‐ Briefly set the context of study and its rationale
  2.  Experimental Approaches -­‐ Summarize approaches without gory details, for instrumentation just state what was measured and why rather than details of how instrument works
  3.  Results -­‐ Summarize what key measurements were collected, be concise and quantitative, picking out only the most important points that connect to the main take-home conclusions of the paper
  4.  Key Findings and Summary -­‐ Summarize key results in context of big picture, give bullet summary of conclusions

The four reviews must be on papers separate from the assigned reading. The review for any given case study area is due one week after we complete that module. This means that you cannot wait until the end of the quarter to submit all four reviews.

Summary of Module Topics and Reading Assignments

Module 1: Molecular Recognition Fundamentals: Thermodynamics and Molecular Interactions

Report Topic -­‐ Biomolecular Stability or Molecular Interactions and Energetics

Case Study Papers

  • Sundberg et al., Biochemistry 39, 15375-­‐15387
  • Pace and Shaw, Proteins: Structure, Function, and Genetics Suppl 4:1-­‐7


  • Clackson and Wells, Science 267, 383
  • Kumar, Tsai, and Nussinov, Protein Engineering 13, 179-­‐191

Learning Objectives

  • Fundamental solution thermodynamics applied to biomolecular interactions and stability
  • Interpretations of enthalpy and entropy in mechanism of biomolecular interactions
  • Major classes of molecular interactions and, where possible, how their energetic contributions can be estimated (van der Waals, electrostatics, H-­‐bonds, hydrophobic effect)
  • How magnitude of molecular contributions can be estimated by site-­‐directed mutagenesis experiments
  • Understanding of ribozyme therapeutics and their mode and target of action

Module 2: Molecular Recognition Fundamentals -­‐ Reaction Kinetics

Report Topic -­‐ Engineered Enzymes

Case Study Papers

  • Gigant et al., PNAS 94, 7857
  • Jackson et al., PNAS 88, 58


  • Wentworth et al., PNAS 93, 799
  • Fersht Chapter on Enzyme Kinetics

Learning Objectives:

  • reaction coordinate, transition state theory, differential affinity of enzymes for transition state versus substrate
  • Interpretation of Michaelis-­‐Menton parameters, their use in determining transition state stabilization contributions to catalytic rate enhancements
  • principles of catalytic antibody generation and mechanism

Module 3: Rational Biotherapeutic Design Report Topic -­‐ PeptidoMimetic Therapeutics Case Study Papers

  • Freire, Archives of Biochemistry and Biophysics, 390, 169–175


  • Joseph-­‐McCarthy, Pharmacology and Therapeutics 84: 179-­‐191
  • Silva, JMB 255,321
  • Wlodawer and Vondrasek, Ann. Rev. Biophys. Biomol. Struct 27:249-­‐84
  • Steinbach chapter

Learning Objectives:

  • Need and impact of rational drug design in pharmaceutical field
  • qualitative understanding of strategies and steps involved in structure-­‐based design
  • Design and characterization of HIV protease inhibitors
  • Relationships between computational approach to energetics and previously covered thermodynamic principles and noncovalent forces

Module 4: Combinatorial Design and Directed Evolution

Report Topics -­‐ Antibody Engineering, Evolution of Enzymes, Nucleic Acid Engineering

Case Study Papers

  • Baca et al., J. Biol. Chem 272:10678
  • Chen and Arnold; 1993 PNAS 90:5618-­‐5622
  • Essler, PNAS 99, 2252


  • Arnold, PNAS 95, 2035
  • Van den Burg, PNAS 95, 2056

Learning Objectives:

  • combinatorial design and affinity maturation approaches to protein engineering
  • principle of directed evolution and applications to enzyme engineering
  • understand how structures captured in directed evolution connected to improved thermodynamic/kinetic properties

Module 5: Cellular Warfare and Immune Surveilance

Report Topics -­‐ Engineered T-­‐Cell Receptors, Molecular Vaccines

Case Study Papers

  • Holler et al., 2000 PNAS 97, 5387-­‐92


  • Steinman and Dhodapkar, Int. J. Cancer 94, 459-­‐473

Learning Objectives:

  • affinity versus specificity in T-­‐cell receptor recognition
  • cell-­‐based approaches to cancer therapy
  • antigen presentation and molecular vaccine design


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