Presenting: Bruce Donald.Introduction to the Course
Reading:
ASMB Preface and ASMB Chapters 1-4.
The Textbook for this class is: Algorithms in Structural Molecular Biology (MIT Press, 2011), also available on Amazon. We call this "ASMB" in these webpages.
Assignment:
Fill out Questionaire.
Please download and install Pymol and King.
I recommend for you the textbooks Brandon and Tooze, Streyer, and CLRS. They are valuable for this class.
Presenting: Bruce Donald.Big Questions in Computational Structural Biology
Reading: Please see the 1/9 Lecture.
Presenting: Bruce Donald.Protein Backbone Geometry, NMR
Pymol Demo
Reading:
No Class, MLK Holiday
Presenting: JJ.KING Demo/Tutorial
Due: Assignment #1
Due: Assignment #2
Reading:
Presenting: Bruce Donald.Nuclear Magnetic Resonance and Structural Biology: Introduction to NOESY and Chemical shifts
Reading:
ASMB Chapters 1-4.
Presenting: Bruce Donald.The Jigsaw Algorithm, Graphs, and Networks in Structural Biology
Due: Assignment #3
Students, to do before class: Solve DLL puzzle posed on Monday!
Students, to do before class: What is the readout of the
(HN,15N)-edited TOCSY experiment?
Primary Reading:
ASMB Chapter 8.
Background Reading (NMR Review):
ASMB Chapters 1-3.
Biological and Biomedical significance of CBFandbeta;: [PDF,
PDB
structure model]
Presenting: Bruce Donald.Dead-End Elimination and Protein Design: Full Sequence Design
Primary Reading: ASMB Chapter 11
PDB id 1FSD, Full sequence design 1 (FSD-1) of beta beta alpha motif, NMR
Background Reading: ASMB Chapters 10 and 9.
Presenting: Bruce Donald.Introduction to Research In Protein Design:
Computational Protein Interface Design, Cystic Fibrosis, and HIV
Reading: ASMB Chapter 12
Zhou, T. et al. Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01. Science 329, 811-817 (2010). PDF
Diskin, R. et al. Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design. Science 334, 1289-1293 (2011).PDF Supplemental Materials
Presenting: Jeff Martin.Structure Determination of Symmetric Protein Complexes
Slides
Reading: ASMB Chapters 15-16, 17.5, and 18.1.4
Background reading: ASMB 15-18
Presenting: Dr. Chittu Tripathy.Structure Determination of Protein Loops, and Ensembles of Loops
Slides
Reading: ASMB Chapters 15-16, 17.1, and 18.1.1
Background reading: ASMB Chapters 24, 15-18
Presiding: Jonathan Jou.Recitation 1
Slides
Reading:
Presiding: Jonathan Jou.Recitation 2
Slides
Due Friday, 2/22/2013: Assignment #4
Reading:
Presenting: Bruce Donald.Drug Design: An Example of Core-Binding Factor Beta
and , the K* Algorithm (with Constant-factor speedup)
Primary Reading:
-
K*: ASMB Chapter 12
and CBFandbeta;: [PDF and PDB structure model]
Background Reading (Design Review): ASMB Chapter 11.
Presenting: Bruce Donald.K* Algorithm (continued), MinDEE, and combinatorial speedup
Reading: K*: ASMB Chapter 12,
plus read ASMB chapters 15-18
Slides
Presenting: Bruce Donald.An Example of Core-Binding Factor, Evidence for the benefit of Continuous Rotamers, Evidence for the benefit of Ensembles.
Reading:
Project Proposals Due
Presenting: Bruce Donald.Issues in Empirical Protein Redesign
Slides
Reading:
- Chen, C.-Y., Georgiev, I., Anderson, A. C. and Donald, B. R. Computational structure-based redesign of enzyme activity.
Proceedings of the National Academy of Sciences 106, 3764-3769 (2009). PDF Supplementary Information
Presenting: Bruce Donald.RDCs and Structure Determination
- Basic Physics and Mathematical
Preliminaries
- Your Friend The Tensor
10:21:51 10:21:59 10:49:02 11:08:52 11:09:04 11:21:06 11:21:15
Reading:
ASMB Chapters 7, 15, 16, 17.3, 18.1.1
Revised Project Proposals Due Friday 3/22
Presenting: Bruce Donald.RDC-based Structure Determiation
Boards: (all times ante meridiem)
10:27:15 10:43:27 11:11:00 11:11:09 11:11:16 Reading:
ASMB Chapters 7, 15, 16, 17.3, 18.1.1
Revised Project Proposals Due Friday
Presenting: Bruce Donald.RDC-based Structure Determiation
Boards: (all times ante meridiem)
10:22:50 10:39:27 11:03:14 11:17:13 Reading:
ASMB Chapters 7, 15, 16, 17.3, 18.1.1
Presenting: Bruce Donald.RDC-based Structure Determiation
Slides
Boards: (all times ante meridiem)
11:04:26 Reading:
ASMB Chapters 7, 15, 16, 17.3, 18.1.1
ConferencesRyan 10:05~10:25
Qing 10:25~10:45
Jae 10:45~11:05
Reading:
ConferencesRyenne 10:05~10:25
Julia 10:25~10:45
Yang 10:45~11:05
Reading:
Presenting: Ryenne and Julia.Probing the Correlation between Deamidation of Aggrecan and Osteoarthritis through a Shotgun Proteomics Approach
Abstract:
Deamidiation of proteins, at the asparagine and glutamine residues, has been shown to reliably indicate age of a protein, a so-called "molecular clock". The deamidataion of a specific protein, aggrecan, has been linked to osteoarthritis, a degenerative joint disease. An algorithm has been developed to predict deamidation sites of the protein and have been validated through the use of mass spectrometry. Determining a correlation between structural stability of the protein and deamidation sites will allow for a more comprehensive understanding of the link between deamidation and osteoarthritis. The stability of the protein will be probed through the Stability of Proteins by Rates of Oxidation (SPROX) protocol.
Slides
Reading:
- Robinson, N. E. and Robinson, A. B. Molecular clocks. Proceedings of the National Academy of Sciences 98, 944-949 (2001).
pdf
- Strickland, E. C. et al. Thermodynamic analysis of protein-ligand binding interactions in complex biological mixtures using the stability of proteins from rates of oxidation. Nature Protocols 8, 148-161 (2012). pdf
Presenting: Ryan.Computational redesign of GtfD from the vancomycin biosynthetic pathway
As multidrug resistant pathogens become increasingly common, the drug of last resort, vancomycin, is called upon with increasing frequency to treat otherwise incurable infections. As a result, some pathogens have developed resistance to even vancomycin, resulting in an increased need for productive drug development. It has been hypothesized that the glycosylation states of antibiotics such as vancomycin play an important role in recognition and effectiveness. In this study, we aim to change the substrate specificity of the glycosyltransferase GtfD from the vancomycin biosynthetic pathway to diversify vancomycin using computational structure-based protein design methods. Reading:
- Mulichak, A. M., Lu, W., Losey, H. C., Walsh, C. T., and Garavito, R. M. (2004). Crystal structure of vancosaminyltransferase GtfD from the vancomycin biosynthetic pathway: interactions with acceptor and nucleotide ligands. Biochemistry, 43(18), 5170-80. doi:10.1021/bi036130c
pdf
- Fu, X., Albermann, C., Jiang, J., Liao, J., Zhang, C., and Thorson, J. S. (2003). Antibiotic optimization via in vitro glycorandomization. Nature biotechnology, 21(12), 1467-9. doi:10.1038/nbt909
pdf
Reading:
Presenting: Yang.Algorithms for building protein ensembles and their applications to a multi-domain protein SpA-N Protein A is a crucial virulence factor in Staphylococcus aureus. The N-terminal half of Staphylococcal Protein A, named as SpA-N, has five IgG-binding domains. SpA-N has segmental flexibility because of four conserved short linkers between the five domains. The flexibility is probably necessary for SpA-N to effectively bind maximally five antibody molecules. Consequently, it is important to experimentally characterize the flexibility or the structure ensemble of SpA-N through efficient algorithms. The goal is to analyze current algorithms and find or design an algorithm for building an ensemble of this specific system.
Reading:
-
Rieping, W., Habeck, M., and Nilges, M. (2005) Inferential structure determination, Science 309, 303-
306.
pdf
-
Richter, B., Gsponer, J., Várnai, P., Salvatella, X., and Vendruscolo, M. (2007) The MUMO (minimal
under-restraining minimal over-restraining) method for the determination of native state ensembles of
proteins, J Biomol NMR 37, 117-135.
pdf
-
Wang, L., and Donald, B. R. (2006) A data-driven, systematic search algorithm for structure
determination of denatured or disordered proteins, In Proceedings of the LSS Computational Systems
Bioinformatics Conference (CSB), pp 67-78.
pdf
Reading:
- Lee, W. et al. Full Reconstruction of a Vectorial Protein Folding Pathway by Atomic Force Microscopy and Molecular Dynamics Simulations. Journal of Biological Chemistry 285, 38167-38172 (2010).
pdf
- Bornschlögl, T. and Rief, M. Single-Molecule Dynamics of Mechanical Coiled-Coil Unzipping. Langmuir 24, 1338-1342 (2008).
pdf
Presenting: Jae.Molecular Dynamic Simulation of P Loop Ejection in HipA
Abstract:
HipA (high persistence A protein) is one of the proteins known to affect persistence of bacteria. Persistence is bacteria avoiding antibiotics by becoming dormant during antibiotic treatment. Then, the dormant bacteria can revert back to the growth phase when the drugs are gone and continue to grow. HipA is believed to be involved in this bacteria's ability to switch back and forth between the dormant and the growth phase. HipA has two conformational states, active and inactive. Active HipA can induce the cells to go into a dormant state, and the conversion to the inactive conformation can allow the cells to revert back to the growth phase. This conversion between two states involves a loop ejection, but the mechanism of how such transition can occur is poorly understood. So this study aims to use molecular dynamic simulation to generate realistic trajectory of the loop ejection. Reading:
- Schumacher, M.A., Piro, K.M., Xu, W., Hansen, S., Lewis, K., and Brennan, R.G. (2009). Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB. Science 323, 396-401.
pdf
- Schumacher, M.A., Min, J.K., Link, T.M., Guan, Z., Xu, W., Ahn, Y.H., Soderblom, E.J., Kurie, J.M., Evdokimov, A., Moseley, M.A., Lewis, K., and Brennan, R.G. (2012). Role of unusual P loop ejection and autophosphorylation in a HipA-mediated persistence and multidrug tolerance. Cell Reports 2, 518-525.
pdf