Computational Protein Design Using AND/OR Branch-and-Bound Search Yichao Zhou Yuexing Zhou Jianyang Zeng Institute for Interdisciplinary Information Sciences Tsinghua University Apr, 2015 Yichao Zhou, Yuexing Zhou, Jianyang Zeng Computational Protein Design Using AND/OR Branch-and-Bound
What is Structure-Based Protein Design? Val Yichao Zhou, Yuexing Zhou, Jianyang Zeng 1D amino acid sequence Ile Ser Ile Trp Ile Ala Pro Asp Ser Gly Glu Protein structure template Pro Gly Gly His Pro Ile Toolbox Backbone Template Energy Functions Rotamer Library Algorithm Design Computational Protein Design Using AND/OR Branch-and-Bound · · · · · ·
Why We Need Protein Design? Applications Figure: New Drug Discovery Figure: Enzyme Optimization Figure: Drug Resistance Prediction Figure: New Biosensor Design Yichao Zhou, Yuexing Zhou, Jianyang Zeng Computational Protein Design Using AND/OR Branch-and-Bound
Protein Design as an Optimization Problem NP Hard! Yichao Zhou, Yuexing Zhou, Jianyang Zeng Self energy of rotamer i r i r i r backbone Energy Function (Optimization Target) Computational Protein Design Using AND/OR Branch-and-Bound rotamer j s rotamer i r E 2 ( i r , j s ) ( E ) 1 i r � � � E T = E 1 ( i r ) + E 2 ( i r , j s ) j s , i < j Pairwise energy between rotamer i r and j s
Protein Design as an Optimization Problem NP Hard! Yichao Zhou, Yuexing Zhou, Jianyang Zeng Self energy of rotamer i r i r i r backbone Energy Function (Optimization Target) Computational Protein Design Using AND/OR Branch-and-Bound rotamer j s rotamer i r E 2 ( i r , j s ) ( E ) 1 i r � � � E T = E 1 ( i r ) + E 2 ( i r , j s ) j s , i < j Pairwise energy between rotamer i r and j s
Search Algorithm [Xu06] Yichao Zhou, Yuexing Zhou, Jianyang Zeng [Yanover02] Propagation Belief Annealing Simulated [Voigt00] Monte Carlo … Algorithm Approx … composition Space Search Tree De- ford05] [Kings- ear Program Integer Lin- [Hong09] and Bound Branch [Leach98] DEE/A* Algorithm Exact Algorithm Computational Protein Design Using AND/OR Branch-and-Bound
Search Algorithm [Xu06] Yichao Zhou, Yuexing Zhou, Jianyang Zeng [Yanover02] Propagation Belief Annealing Simulated [Voigt00] Monte Carlo … Algorithm Approx … composition Space Search Tree De- ford05] [Kings- ear Program Integer Lin- [Hong09] and Bound Branch [Leach98] DEE/A* Algorithm Exact Algorithm Computational Protein Design Using AND/OR Branch-and-Bound
Traditional Branch-and-bound Search Space -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree rooted at x . Heuristic function -17 -22 -31 -32 -29 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: ∞ ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: ∞ ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: ∞ ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Traditional Branch-and-bound Search -34 Yichao Zhou, Yuexing Zhou, Jianyang Zeng nodes in the subtree root at x . Heuristic function -17 -22 -32 -29 -31 -35 -36 -25 -30 -30 -32 -37 -37 Computational Protein Design Using AND/OR Branch-and-Bound Current Best: − 37 ⇒ Residue 1 ⇒ Residue 2 ⇒ Residue 3 Heuristic function h ( x ) returns a lower bound of the energy of leaf
Residue Interaction Network Approximation Simplify the energy model by only considering the interaction between residues whose energy term is greater than a threshold. Approx. Yichao Zhou, Yuexing Zhou, Jianyang Zeng Computational Protein Design Using AND/OR Branch-and-Bound
Problem of Traditional Branch-and-bound Figure: Residue Interaction Network + VS Yichao Zhou, Yuexing Zhou, Jianyang Zeng Computational Protein Design Using AND/OR Branch-and-Bound
Problem of Traditional Branch-and-bound Figure: Residue Interaction Network + VS Yichao Zhou, Yuexing Zhou, Jianyang Zeng Computational Protein Design Using AND/OR Branch-and-Bound
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