Mohamed Raef Smaoui1, Henri Orland2, Jérôme Waldispühl1. 1. School of Computer Science and McGill Center for Bioinformatics, McGill University, Montreal, QC, Canada and. 2. Institut de Physique Théorique, CEA-Saclay, 91191 Gif/Yvette Cedex, France.
Abstract
MOTIVATION: Amyloids play a role in the degradation of β-cells in diabetes patients. In particular, short amyloid oligomers inject themselves into the membranes of these cells and create pores that disrupt the strictly controlled flow of ions through the membranes. This leads to cell death. Getting rid of the short oligomers either by a deconstruction process or by elongating them into longer fibrils will reduce this toxicity and allow the β-cells to live longer. RESULTS: We develop a computational method to probe the binding affinity of amyloid structures and produce an amylin analog that binds to oligomers and extends their length. The binding and extension lower toxicity and β-cell death. The amylin analog is designed through a parsimonious selection of mutations and is to be administered with the pramlintide drug, but not to interact with it. The mutations (T9K L12K S28H T30K) produce a stable native structure, strong binding affinity to oligomers, and long fibrils. We present an extended mathematical model for the insulin-glucose relationship and demonstrate how affecting the concentration of oligomers with such analog is strictly coupled with insulin release and β-cell fitness. AVAILABILITY AND IMPLEMENTATION: SEMBA, the tool to probe the binding affinity of amyloid proteins and generate the binding affinity scoring matrices and R-scores is available at: http://amyloid.cs.mcgill.ca
MOTIVATION: Amyloids play a role in the degradation of β-cells in diabetespatients. In particular, short amyloid oligomers inject themselves into the membranes of these cells and create pores that disrupt the strictly controlled flow of ions through the membranes. This leads to cell death. Getting rid of the short oligomers either by a deconstruction process or by elongating them into longer fibrils will reduce this toxicity and allow the β-cells to live longer. RESULTS: We develop a computational method to probe the binding affinity of amyloid structures and produce an amylin analog that binds to oligomers and extends their length. The binding and extension lower toxicity and β-cell death. The amylin analog is designed through a parsimonious selection of mutations and is to be administered with the pramlintide drug, but not to interact with it. The mutations (T9K L12KS28HT30K) produce a stable native structure, strong binding affinity to oligomers, and long fibrils. We present an extended mathematical model for the insulin-glucose relationship and demonstrate how affecting the concentration of oligomers with such analog is strictly coupled with insulin release and β-cell fitness. AVAILABILITY AND IMPLEMENTATION: SEMBA, the tool to probe the binding affinity of amyloid proteins and generate the binding affinity scoring matrices and R-scores is available at: http://amyloid.cs.mcgill.ca
Authors: Juris J Meier; Rakez Kayed; Chia-Yu Lin; Tatyana Gurlo; Leena Haataja; Sajith Jayasinghe; Ralf Langen; Charles G Glabe; Peter C Butler Journal: Am J Physiol Endocrinol Metab Date: 2006-07-18 Impact factor: 4.310
Authors: Matthew Riddle; Juan Frias; Bei Zhang; Holly Maier; Carl Brown; Karen Lutz; Orville Kolterman Journal: Diabetes Care Date: 2007-08-13 Impact factor: 19.112
Authors: Jed J W Wiltzius; Stuart A Sievers; Michael R Sawaya; Duilio Cascio; Dmitriy Popov; Christian Riekel; David Eisenberg Journal: Protein Sci Date: 2008-06-12 Impact factor: 6.725
Authors: Allen W Bryan; Matthew Menke; Lenore J Cowen; Susan L Lindquist; Bonnie Berger Journal: PLoS Comput Biol Date: 2009-03-27 Impact factor: 4.475