A Biophysical View of Biology, AS.020.382
Robert Schleif, Professor
TTh 1:30-2:45, Covid vulnerability necessitates that the course be online. Email the instructor for a zoom link.
Prerequisites: prior courses in calculus, physics, genetics or a willlingness to learn topics in these areas as needed to understand the course material.
The objective of this course is to develop in students a strong, intuitive, and physically based sense of how fundamental biological processes work, how these processes are interrelated, and how they are the simple consequence of simple physical principles. The course will consider the sizes, shapes, motions, interactions, and cellular functions of biological molecules. The course should bring together material covered in multiple, diverse courses.
Major topics to be considered will include cell and population growth, diffusion, binding and dissociation kinetics, the qualitative and quantitative aspects of the synthesis, structure, and function of proteins and nucleic acids. The basic, and inherently simple bases for structure determination, and several topics in the analysis of experimental data will also be considered. Effort will be taken to relate physical results to biological and medical problems and phenomena.
Typically, a class will begin by my addressing students' questions related to the previous classes. Then, I may ask additional questions ask concerning the previous class or specifically what you learned in your reading about the topic, i.e. "Mary, in connection with the topics of the previous class, what did you read about and tell me something interesting that you learned." Ordinarily, about three main points or topics will be covered in each class. I will first outline or place the point in context, and then, in response to the answers given by students, the point will be developed. During this period, students may also ask additional questions. After the formal development of a point, usually we will take a five minute breather, and then have a five to ten minute in class discussion, perhaps stimulated by a leading question or two. When I ask questions of the class, generally I will randomly choose students rather than pick a volunteer whose hand is up (see below).
If we have to go to remote rather than in-class, I would like everyone to have their video cameras on and their microphones off. When you wish to speak, turn your audio on, and I should notice it and recognize you. If I'm not seeing it, say something. When you are finished, please turn your microphone off again. When the class is finished, you may, if you wish, remain connected and we will proceed as if you had come up to me after an in-class session and asked some questions.
Often the pathway for covering a topic will depend on questions and answers from students during the class session. Thus, I will not be using PowerPoint and prepared slides or videos, but instead, speaking and writing material on the blackboard. As I discuss and present material, at times, I will ask something about the material at that point, and often the answer will determine what I write and explain next. During the presentation, questions from students are welcome and will also determine the course of the presentation. Therefore, everyone should come to class expecting to, and ready to participate in the discussions. Occasionally, a class may veer completely off the intended subject, which will then be taken up in the next class session.
No textbook will be used and there will be only a few specific recommendations for outside reading. Instead, students are expected to find their own material, suitable to their level of understanding and background. Most often this will come from the internet or materials used in prior courses. This material should augment material covered in class. Occasional specific homework problems will be suggested and will be discussed in class.
I hope that in class discussion will be sufficient for me to assess the extent to which everyone is grasping the material and extending their understanding. If not, I will likely assign each person a different topic for a very short paper to be prepared in the final two weeks of the course.
Topics to be covered, suggested pre class study topics, post class study topics
1. Growth, exponential and chaotic, balanced growth, approach to steady state, game of Life.
Before class: the exponential function in calculus
2. Sizes of things, what cell interior looks like, how to determine internal cell conditions
Before class: Draw circles with size to scale for water, DNA diameter, and a large protein complex like RNAP
Think about how to infer a cell's internal pH and ion concentrations
After class: Chaos problem
3. Times to diffuse in cells, cells need motors, how to make molecular motors, Brownian ratchets, random walks
Before class: how do things get around in cells
After class: simulate a random 1D walk using a spreadsheet
4. Size separation by diffusion (Brownian ratchet), random walks, diffusion is a random walk, derivation of diffusion equation, flow rate to a black hole
5. Solution to diffusion equation, application of flow rate to a black hole, time to find a target on DNA, maximum theoretical rate of DNA elongation, actually measuring DNA elongation rate
Before class: what are the experimental problems in measuring DNA elongation rates
6. Rate of protein synthesis, how to measure, graphical extraction of information from E(t) data, when does a protein fold?
Before class: what is the elongation rate of protein
7. Completion of induction kinetics. Least squares curve fitting. A little about DNA structure, electrophoresis of DNA, cellular importance of proteins binding to DNA, salt dependence of proteins binding to DNA
8. Reaction rates and equilibrium, Michaelis-Menton or Langmuir, extracting information from binding curves, real example
9. How to measure binding, maximum theoretical binding rate, some proteins exceed this, how?
10. Hemoglobin and cooperativity, why cooperativity is useful, other situations for cooperativity
11. General case of "cooperativity", simplifications of general case, Hill, Monod Wyman Changeux, Koshland Nemethy
12. Determination of mechanism of a ligand dependant DNA binding protein, derivation of Boltzman distribution (exponential preference for lower energy state) and its use in understanding binding and reaction rates.
13. Extending Boltzman to account for numbers of states leads to definition of entropy. Rewriting Boltzman now gives basic thermodynamics.
14. Chelate effect is everywhere in biology. What it is. Dimer binding affinity in terms of monomer binding affinity.
15. Arabinose operon, positive and negative regulation. DNA looping, how it was discovered and how it was demonstrated. Its importance in biology.
16. Fundamental limitations on accuracy of amino acid identification during protein synthesis. Experimental determination of accuracy of protein synthesis. Kinetic proofreading and how to be arbitrarily accurate.
17. Amino acid structure and protein structure, Ramachandran plot
18 Nov.2. Examine protein structure with PyMol
Before class download the protein graphics display program PyMol. Familiarize yourself with the use of the program to display a protein structure, say of AraC protein, whose Protein Data Bank identifier is 2ARC. Learn how to do something interesting as in class students will be asked to share their screen of PyMol with the class and demonstrate their interesting feature. A few examples might be: color amino acids according to hydrophobicity or acidity or their vibration amplitudes in the X-ray structure determination (B value), identify the residues touching a particular residue, display in cartoon form, make random coil regions fatter, RMS overlay a subunit from the plus and minus arabinose structures, measure distance between two residues, "mutate" one residue to a different amino acid residue, look at the rotamers of an amino acid, build a Ramachandran plot.
19 Nov. 4. Determination of protein structure, X-ray, NMR. Cryo EM
20 Nov.9. Prediction of protein structure, neural networks, AlphaFold
21 Nov. 11 Identifying similar protein and DNA sequences and aligning them
22 Nov. 16. Protein dynamics and molecular dynamics
23 Nov. 18. DNA structure, reading sequence from double helix, supercoiling
24 Nov. 30. Bayesian statistics and its use in biology
25 Dec. 3. Before class students are to decide what were the major points (1-4) of each class and write a couple sentences about them. Then, in class, we will go through the classes in order and I will randomly pick students to tell what they felt the major points were and a few words about them. I may augment some of these explanations with my description of what I wanted to be the major points and something about their importance.
Revised Nov. 10/2021