Biochemistry & Molecular Biology ! Departmental Retreat October 7, 2016; Okemos Conference Center ! Sebastian Raschka Leslie A. Kuhn Lab Detecting the Native Ligand Orientation by Interfacial Rigidity 

Binding Mode Prediction Crystal structure of the complex between carboxypeptidase A and the biproduct analog inhibitor L-benzylsuccinate (PDB code: 1cbx) 

near-native binding mode → rigid binding pocket “bad” docking → flexible binding pocket Hypothesis 

Chorismate mutase and prephenate (PDB code: 1com) ProFlex: D. J. Jacobs, A. J. Rader, L. A. Kuhn, and M. F. Thorpe (2001) Protein Flexibility Predictions Using Graph Theory. Proteins: 44, 150-165 . near-native binding mode → rigid binding pocket “bad” docking → flexible binding pocket 

APO HOLO 

2.8 Å RMSD 1.0 Å RMSD Crystal Pose Crystal structure of the complex between carboxypeptidase A and the biproduct analog inhibitor L-benzylsuccinate (PDB code: 1cbx) 

Ligand Pose RMSD (Å) Number of Complexes 

Ligand Pose RMSD (Å) Number of Complexes 

Ligand Pose RMSD (Å) Number of Complexes 

APO SET Number of Complexes Ligand Pose RMSD (Å) 

3.  New information / signal (cooperativity) 1.  Competitive scoring function for binding mode prediction / docking 2.  Robust, no “bad” predictions 

http://www.kuhnlab.bmb.msu.edu/software https://psa-lab.github.io/siteinter lock ite nterlock S I R a s c h k a , Bemister- Buf fi ng ton , an d Ku hn 2 0 1 6 . P r o t e i n s . D O I : 1 0 . 1 0 0 2 / p r o t . 2 5 1 7 2. (In press.) 

PROTEIN STRUCTURE AND ANALYSIS LAB Dr. Leslie Kuhn (Lab. Director) Joseph Bemister-Buffington (Undergrad. Researcher) Alex Wolf (Undergrad. Researcher) http://www.kuhnlab.bmb.msu.edu 

THANK YOU 

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Chao-Yie Yang R, Wang A, Wang S. A Systematic analysis of the effect of small-molecule binding on protein flexibility of the ligand- binding sites. J Med Chem 2005;5648–5650. 

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