backbone motion in protein design
DESCRIPTION
Backbone Motion in Protein Design. Andrew Leaver-Fay University of North Carolina at Chapel Hill David O’Brien, Kimberly Noonan, Jack Snoeyink. Protein Design. Create an amino acid sequence that adopts a desired conformation Binds a desired small molecule Catalyses a desired reaction. - PowerPoint PPT PresentationTRANSCRIPT
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Backbone Motion in Protein Design
Andrew Leaver-Fay
University of North Carolina at Chapel Hill David O’Brien, Kimberly Noonan, Jack Snoeyink
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Protein Design
• Create an amino acid sequence that adopts a desired conformation– Binds a desired small molecule– Catalyses a desired reaction
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Dezymer
From Homme Hellinga’s Lab
• Use backbone of a known protein as a scaffold– Hang different sidechains from original C
• Sample the sidechain conformation space– Rotamer library
• Sample the ligand conformations inside binding pocket
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Dezymer
• Combinatorial optimization– Find the best combination of rotamers to pack
around the ligand of interest.
• Dead End Elimination– Technique for pairwise-decomposable energy
functions
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Why Move Backbones?
• We know backbones move.
Mooers et.al. (2003) JMB 332, 741-56Courtesy of Jane Richardson
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Why Move Backbones?
• Increase power of design tools– Small motions can allow more rotamers to fit at a
given location Now search a larger sequence space.
– Understand more completely the result of sequence selection on backbone motion
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Tools for Backbone Motion
• PROBIK @ UNC– Small motions for short backbone segments– Offers
• Motion Derivative Vectors• Matlab Interface
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Incorporating Backbone Motion
• Generate Backbones Offline– Feed them into Dezymer
• Goal: Incorporate motions into DEE itself
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Success of Dezymer
• TNT Binding Protein– 2 nM Kd
• R3– Ribose Binding Protein (2dri) scaffold
• Relaxed by molecular dynamics– Forces two phenylalanine rings in the binding pocket
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R3 – Case Study
• Model of R3s structure is imperfect– Multiple Bad (>0.4 A) Overlaps– Phenylalanine rings un-stacked.
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R3 – Case Study
• Use backbone motion to better explain R3’s success
• Suggest sequence modifications for more powerful receptors
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R3 – PHE 190
• Small motion from 189 N-Ca-C Bond angle
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R3 – Preliminary Results
• Dezymer result after PHE 190 BB Motion
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R3 – PHE 15 / PRO 237
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R3 – SER 215
• Ramachandran Outlier in Original Conformation