University:
Boston University
Course:
CAS BI 525 | Biology of Neurodegenerative Diseases
Academic year:

2023
Views:

152

Pages:

19
Author:

emprarnh0s

Bulged torso structures share similar sequences D Y F R A D Y The bulged torso sequence motif is germline encoded Bulged Consensus Germline Consensus Antibody Structure Prediction • RosettaAntibody • http://rosie.rosettacommons.org/antibody/ • Kotai Antibody Builder • https://sysimm.ifrec.osaka-u.ac.jp/kotaiab/ • PIGS (Prediction of ImmunoGlobulin Structures) • http://circe.med.uniroma1.it/pigs/ • ABodyBuilder • http://opig.stats.ox.ac.uk/webapps/sabdab-sabpred/Modelling.php Antibody/Antigen Docking Ab Ag Coarse Grained Docking Docking Refinement Binding Types Antibody Specific Issues: VH-VL Caveats  Rigid body docking may be highly loop dependent  Working with ensembles of models may help  Glycosylation can be an issue. Antibody Docking • Rosetta SnugDock • http://rosie.rosettacommons.org/snug_dock/ • PIPER with the ADARS potential • https://www.schrodinger.com/piper • ZDOCK with Antibody i-Patch potential • http://zdock.umassmed.edu/ (Inverse) Protein Folding Problem Holy Grail of Comp. Struct. Biology Y D T R P I E H K F S AW Protein Folding Problem Sequence Structure Inverse Folding Problem  Given a protein’s AA sequence, what is its 3-dimensional fold , and how does it get there?  Assume 100 conformations for each amino acid in a 100 amino acid protein  10200 possible conformations!  Cyrus Levinthal’s paradox of protein folding,1968.  Given a protein fold, which primary sequence(s) fold into it?  Assume a total of 100 conformations for all 20 natural occurring amino acids side chains in a 100 amino acid protein  10200 possible conformations!  Earth is less than 1010 years old. Sidechain Degrees of Freedom All Likely Side Chain Conformations are Present in the Protein Databank  Lysine has four side chain χ-angles  Serine has one side chain χ-angle H OH Cα Ni Cβ H H Ci H Ni H Cα Cβ OH H Ci H Ni H Cα Cβ H OH Ci Sampling and Scoring for Side Chain Repacking and Design Local Rotamer Bias Approximate interactions within sidechain using the distribution of sidechain conformations (rotamers) seen in known protein structures Simulated Annealing Monte Carlo energy minimization Dahiyat, B. I. and Mayo, S. L. (1997) Science, 278, 82-7 Dunbrack, R. L., Jr. and Karplus, M. (1993) J Mol Biol, 230, 543-74. Kuhlman, B., et. al. (2003) Science, 302, 1364-1368. Energy function Statistically derived potential function •VDW interaction •solvation •hydrogen bonding potential •pair wise interactions •rotamer probability Repack Amino Acid Side Chains by MC search in Rotamer Library 10 June 2018 © Jens Meiler Designed Model (blue) and X-ray Structure (red) of Top7 Kuhlman, B.; Dantas, G.; Ireton, G. C.; Varani, G.; Stoddard, B. L.; Baker, D. "Design of a Novel Globular Protein Fold with Atomic Level Accuracy" Science 2003, 302, 1364-1368. Combinatorial Optimization Assumes a Fixed Backbone. random perturbation of one or several backbone torsion angles fast side-chain optimization using a rotamer representation gradient-based minimization with respect to backbone and side chain torsion angles Enhancing Polyspecificity: Multistate Design REstrained CONvergence multi-specificity design (RECON) Willis, J. R. et al. PLoS Comput Biol; 2013; 9 (4):e1003045. Sevy, A. et al. PLoS Comput Biol. 2015; 11(7):e1004300