Non-covalent protein-ligand iN         l       i li d interactions?                                 i ?Easy as π          ...
π hides a wealth of complexity                                                        cIt is the ratio of circumference (c...
Presentation Overview: The What, Why, and How of it allWhat are we trying to do?    Perform a detailed investigation of π-...
Why are π-π interactions important?    Prevalent dispersive driven interactions    Structurally d    St t ll and energetic...
Why are π-π interactions important?Viramune® (nevirapine)                                                                 ...
Relibase+[3] Search Query    Filtering Criteria:                                   Focused on compounds of these          ...
Heteroatom Count ( # of Ring systems found in data set)                 Motif          Histidine   Phenylalanine      Tyro...
Non-covalently Bound Set (Histidine)          Two distinct clusters          1. “T-shaped”              T shaped          ...
Non-covalently bound Amino Acid Set                                HIS        PHERadius:       3.0Å ≤ x ≤ 5.0Å            ...
How did we use MOE?Custom MOE browser•   Review complexes from PDB•   Automatically prepare Q-CHEM[4] input       —   CCSD...
What do the results tell us?                      A little more than we could possibly understandShape: Position with resp...
Density Functional Theory (DFT) and Dispersion    DFT is formally exact in the ground state, if    the exact form of EXC[ρ...
Density Functional Theory (DFT) and Dispersion                                                                            ...
Dig into the data[7]                                                      Above (A)           Below (B)            Below (...
AM1 Dipole Moment versus ωB97X-D for pyrimidine                   containing systems                                      ...
Outlook and Future WorkRobust workflow in place to extract π-π interactions and torun QM calculations within our HPC envir...
Cultural Highlight                                                    Ethnographic examination of                         ...
Acknowledgements Dr. Sandy Farmer Dr. Miguel Teodoro Dr. Bryan McKibben                      18
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Non-covalent protein-ligand interactions? Easy as Pi

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This is a presentation made at the Chemical Computing Group UGM in 2010. The work describes a collaboration with a talented summer intern, wherein we looked at the challenging problem of non-covalvent protein-ligand interactions

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Non-covalent protein-ligand interactions? Easy as Pi

  1. 1. Non-covalent protein-ligand iN l i li d interactions? i ?Easy as π Jonathan Lai David C. Thompson Ming Hong-Hao Ingo Mügge
  2. 2. π hides a wealth of complexity cIt is the ratio of circumference (c) to diameter (d) c d =It is an irrational number dIt is a transcendental number 3. 1415926535 8979323846 26433832 795028841971 6939937510 58209749 445923078164 0628620899 86280348It occurs in lots of interesting places: 253421170679 8214808651 32823066 470938446095 5058223172 53594081• Normalization of the normal distribution 284811174502 8410270193 85211055 596446229489 5493038196 44288109• Distribution of the primes 756659334461 2847564823 37867831 652712019091 4564856692 34603486 104543266482 1339360726 02491412• Buffon’s needle problem 737245870066 0631558817 48815209 209628292540 9171536436 78925903• The Bible (I Kings 7:23 and Chronicles 4:2) 600113305305 4882046652 13841469 519415116094 3305727036 57595919 530921861173 8193261179 31051185 480744623799 6274956735 18857527 π is tricky. So are π-π molecular interactions ππ 248912279381 8301194912 . . . 31 August 2011 2
  3. 3. Presentation Overview: The What, Why, and How of it allWhat are we trying to do? Perform a detailed investigation of π- π stacking interactions between heterocyclic ring systems and aromatic amino acid side-chainsWhy are we trying to do it? Could we preferentially suggest heterocycles for synthesis? Can we extract any generalities about geometry?How are we going to do it? Extract deposited structural information from the PDB Evaluate interactions using ab initio methodologies 3
  4. 4. Why are π-π interactions important? Prevalent dispersive driven interactions Structurally d St t ll and energetically i ti ll important i t and i t t t inter- d intra-molecular l l interactions[1] Sandwich T-shaped Parallel Displaced -1.33 k l/ l[2] 1 33 kcal/mol -2.24 k l/ l[2] 2 24 kcal/mol -2.22 kcal/mol[2] 2 22 k l/ l[1] A Medicinal Chemist’s Guide to Molecular Interactions, Caterina Bissantz, Bernd Kuhn, Martin Stahl JMC, Article ASAP (2010)[2] M. O. Sinnokrot, and C. David Sherrill, J. Phys. Chem. A, 110, 10656-10668 (2006) [CCSD(T) / aug-cc-pVDZ (carbon) / cc-pVDZ (hydrogen)] 4
  5. 5. Why are π-π interactions important?Viramune® (nevirapine) O Distance: 4.43Å Tilt Angle: 16.88° C NH2 HO CH ΔIE E : -1.38 kcal/mol Est. H2CNevirapine Tyrosine OH1VRT.pdb O HN N N N 11-cyclopropyl-5,11-dihydro-4-methyl -6H-dipyrido[3,2-b:2,3-e] 6H dipyrido[3,2 b:2 ,3 e] [1,4]diazepin-6-one 5
  6. 6. Relibase+[3] Search Query Filtering Criteria: Focused on compounds of these motifs: • π-π stacking interactions ki i i N N N N N • Crystals w/ resolutions: ≤ 2.5Å N N N • Not nucleic acids • No duplicates by PDB ID Ignored substituents • Aromatic, planar ligands Excluded compounds of these motifs: O O Geometric Filtering criteria: Radius: 3.4Å ≤ x ≤ 4.1Å N Tilt angle: 0 ≤ x ≤ 40° Ring pucker: |x| ≤ 5° N O[3] Relibase+, v2.2 6
  7. 7. Heteroatom Count ( # of Ring systems found in data set) Motif Histidine Phenylalanine Tyrosine Tryptophan 136 114 93 94 45 67 165 82 98 307 212 101 Pyrazine (1 4 P i (1,4 0 11 4 4 diazine), Triazine, and OthersRadius: 3.4Å ≤ x ≤ 4.1ÅTilt angle: 0 ≤ x ≤ 40°Ring pucker: |x| ≤ 5° 7
  8. 8. Non-covalently Bound Set (Histidine) Two distinct clusters 1. “T-shaped” T shaped 2. “Sandwich/Displaced sandwich” p Conformations between clusters are still accessible (e.g. radius ~ 4.5Å, tilt angle ~ 30 ) (e g 4 5Å 30°) Can still extract a wealth of information (e g (e.g. ligand orientation, minimum contact distance)Radius: 3.0Å ≤ x ≤ 5.0ÅTilt angle: 0 ≤ x ≤ 80°Ring pucker: |x| ≤ 5° 8
  9. 9. Non-covalently bound Amino Acid Set HIS PHERadius: 3.0Å ≤ x ≤ 5.0Å TYR TRPTilt angle: 0 ≤ x ≤ 80°Ring pucker: |x| ≤ 5° 9
  10. 10. How did we use MOE?Custom MOE browser• Review complexes from PDB• Automatically prepare Q-CHEM[4] input — CCSD(T) / aug-cc-pVDZ basis — Account for BSSE (EAB, EA, and Eb)• Triage to ensure correct bond orders• Interface with HPC environment for job submission[4] Q-CHEM, v3.2 10
  11. 11. What do the results tell us? A little more than we could possibly understandShape: Position with respect to plane of His. (Below) (Above)Size & Colour: CCSD(T) Energy (kcal/mol) [Small and red is a very attractive interaction] 11
  12. 12. Density Functional Theory (DFT) and Dispersion DFT is formally exact in the ground state, if the exact form of EXC[ρ] is known • It is not DFT migrated from solid-state physics into the chemistry community to great effect y y g D • Local density approximation works well for materials, not so well for molecules • Add non-locality to better approximate inhomogeneity of molecular density – Perdew’s ‘Jacob’s Ladder of functionals’ There are a number of well-known issues involving DFT, including its inability to deal with dispersion[5][5] C. David Sherrill, J. Chem. Phys., 132, 110902 (2010) 12
  13. 13. Density Functional Theory (DFT) and Dispersion 1 CCSD(T) / kcal/mol 0 -4.5 -3.5 -2.5 -1.5 -0.5 0.5 1.5 -1 ωB97X-D[6] / kcal/mol -2 R R² = 0.941 -3 D -4 -5[6] Jeng-Da Chai and Martin Head-Gordon, Phys. Chem. Chem. Phys. 10, 6615 (2008) -6 6 13
  14. 14. Dig into the data[7] Above (A) Below (B) Below (C)Above (45) Volumetric clustering l t i Below (B)Below (52)• Focus on pyrimidine (98 structures) Below (C)• Use volumetric clustering Correlation with overall dipole?[7] boyd, danah. 2010. "Privacy and Publicity in the Context of Big Data." WWW. Raleigh, North Carolina, April 29 14
  15. 15. AM1 Dipole Moment versus ωB97X-D for pyrimidine containing systems AM1 Dipole Moment 0 1 2 3 4 5 6 -1 -2ωB97X kcal / mol -3 X-D -4 R² = 0.6402 -5 -6 6 Electrostatic component masks dispersive interaction, making our quest for a canonical geometry somewhat redundant 15
  16. 16. Outlook and Future WorkRobust workflow in place to extract π-π interactions and torun QM calculations within our HPC environment • π-π iinteractions tend to b di l d sandwiches i d be displaced d ih • Potential energy surface is shallow • Calculating and analyzing interaction potential energy surface g y g p gy is challenging • ωB97X-D appears to be a viable alternative to CCSD(T) • Substantial electrostatic component to interaction energy — Correlation of pyrimidine energy with total AM1 dipole momentSelect suitable, representative, displaced sandwich geometryand evaluate heterocyclic systems 16
  17. 17. Cultural Highlight Ethnographic examination of ‘financiers’ financiers — Investment bankers — Risk managers — Fund managers “All models are wrong, but some models are useful” – G. E. P. Box useful “If exactitude is elusive, it i better to be tit d i l i is b tt t b approximately right than certifiably wrong” – B. B. MandelbrotThe Big Short, Michael Lewis, W. W. Norton (2010)
  18. 18. Acknowledgements Dr. Sandy Farmer Dr. Miguel Teodoro Dr. Bryan McKibben 18

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