Exploring Energy and Fitness Landscapes of Proteins

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Florence Hancock
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Protein-Ligand Binding: structure based drug design!

1 Exploring Energy and Fitness Landscapes of Proteins! Computer Simulations in Chemistry and Biophysics! Protein-Ligand Binding: structure based drug design! HIV Family and Kinase Family Protein Targets! Temple Grid Computing, the World Community Grid (IBM)

2 Binding Free Energy Predictive Models [Gallicchio and Levy, Adv. Prot. Chem (2012)] Double Decoupling Method (DDM) Relative Binding Free Energies (FEP) λ-dynamics Potential of Mean Force/ Pathway Methods Docking & Scoring Statistical mechanics theory BEDAM (Implicit solvation) Exhaustive docking MM/PBSA Mining Minima (M2) Binding Energy Distribution Analysis Method

3 Entropically favored Statistical Thermodynamics Theory of Binding [Gilson, McCammon et al., (1997)] Binding energy of a fixed conformation of the complex. W(): solvent PMF (implicit solvation model) Ligand in binding site in absence of ligand-receptor interactions

4 Free Energy of Binding = Reorganization + Interaction BEDAM accounts for both effects of interaction and reorganization Docking/scoring focus on ligand-receptor interaction interaction Interatomic interactions

SAMPL4 2013 Temple E. Gallicchio, N. Deng, P. He, R.

5 SAMPL Temple E. Gallicchio, N. Deng, P. He, R. Levy Scripps - A. Perryman, S. Forli, D. Santiago, A. Olson,!

HIV LIFE CYCLE 1 Binding HIV binds to the CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. 2 Fusion HIV fuses with the host.

6 HIV LIFE CYCLE 1 Binding HIV binds to the CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. 2 Fusion HIV fuses with the host. 3 Uncoating Disintegration of the nucleocapsid and the release of virus's RNA 4 Reverse transcription Viral enzyme reverse transcriptase converts the ssrna to a dsdna. 5 Integration Viral enzyme Integrase" fuses the HIV DNA within the host cell's own DNA. 6 Transcription provirus uses a host enzyme called RNA polymerase to make long chains of HIV protein. INTEGRASE 7 Assembly HIV enzyme called protease cuts the long chains of HIV proteins into smaller individual proteins. 8 Budding Newly assembled virus pushes out ("buds") from the host cell.

7 HIV Integrase as a drug target 140S loop Allosteric site Allosteric site Fragment site

Large-Scale Screening by Binding Free Energy Calculations: HIV-Integrase LEDGF Inhibitors!

development of LEDGF binding inhibitors could lead to novel HIV therapies IN/LEDGF Binding Site 450 SAMPL4 Ligand Candidates ~350

......... -5!SAMPL4 blind challenge: computational prediction of undisclosed experimental screens.

8 Large-Scale Screening by Binding Free Energy Calculations: HIV-Integrase LEDGF Inhibitors! HIV-IN is responsible for the integration of viral genome into host genome.!the human LEDGF protein links HIV-IN to the chromosome!development of LEDGF binding inhibitors could lead to novel HIV therapies IN/LEDGF Binding Site 450 SAMPL4 Ligand Candidates ~350 scored with BEDAM Docking + BEDAM Screening !SAMPL4 blind challenge: computational prediction of undisclosed experimental screens.!docking provides little screening discrimination: everything binds! (but useful for prioritizing)!much more selectivity from absolute binding free energies!bedam predictions ranked first among 23 computational groups in SAMPL4,!5 x fold enrichment factor in top 10% of focused library

9 Structural insights from SAMPL4, Avexa Series Compounds P2 (Avexa) P1 (Boehringer Inghelheim) BC-[#&!?W<& Benzodioxole carboxylic acid core =6#"80#"%*<8&%* E170/H171 Structural/energetics requirements for binding: 1. Formation of correlated H-bonds with H171/E170/T Hydrophobic enclosure at P1 pocket (Leu102, Ala128, Ala129,Trp132,Met178), 3. Optionally, occupancy at the P2 pocket (Glu95,Tyr99Thr125,Lys173). 4. Reorganization penalty must be relatively small.

10 Conclusions BEDAM: The Binding Energy Distribution Analysis Method is a method based on statistical mechanics to predict protein-ligand binding affinities In the SAMPL4 competition where we placed first among all the computational groups, we predicted the binding free energies of ~350 ligands to the HIV target protein Integrase. We achieved a 5X enrichment, there is room to improve We are collaborating with groups at the Scripps Research Institute and Ohio State to design lead compounds which will be effective against AIDS target proteins The Computational Challenge Free energy simulations via Grid Computing Gallicchio, Levy; Advances in all atom sampling methods for modeling protein-ligand binding affinities. Curr. Op. Struct, Biol. 21, (2011)

TUGrid Grid computing Decentralized computing.

11 TUGrid Grid computing Decentralized computing. Combining resources owned by multiple parties, in multiple locations, often making use of volunteered resources (PCs). Extremely scalable, with very high computing throughput and low inter-node communication. $%$#&' &'(%./"*,%!"!"#$% #%&'(%)*+",% -*"%$+)% TUGrid Thousands of TU CPUs when not in use by students. ()$%'&,% (%0(%1+2,% &/3-45#67%% *+,(-'' /8%59*%5#3*% IBM s World Community Grid: FightAIDS@Home Phase II Scripps + Temple University Millions of volunteered CPUs from around the world.

News. Volume 8: November 2, 2009

News. Volume 8: November 2, 2009 FightAIDS@Home News Volume 8: November 2, 2009 The FightAIDS@Home Project uses the volunteered computing power of the World Community Grid to test candidate compounds against the variations (or mutants