The Hepatitis B Capsid through the Computational Microscope Jodi A. - PowerPoint PPT Presentation

The Hepatitis B Capsid through the Computational Microscope Jodi A. Hadden University of Delaware Blue Waters Symposium 2019 1

I use Blue Waters to… • Study HBV capsid as a drug target • HBV causes severe liver disease • 250 million people infected • Vaccine, but no cure • Capsid is attractive drug target 2

Hep epatit itis is B B Vi Virus Capsid id 12 vertices 20 faces Lipid membrane Surface proteins 30 edges Capsid DNA A B C D 3

Microsec econd s simula lation a at native e conditions Capsid subunit Drug molecule Assemble using symmetry rules; Parameterization Model in missing protein fragments Drug molecule Complete capsid with force field parameters Crystallography Drug-bound capsid Assign protonation states for environmental pH of 7.0 Native drug-bound capsid Place ions around capsid based on electrostatics Native drug-bound capsid with neutral charge Add bulk water and ions Native drug-bound capsid MD simulation of 6 M atoms in 150 mM NaCl solvent box for 1 μs without restraints 4

Global C l Capsid F Flexib ibili lity 5 Hadden (2018)

Capsid A Asymmetry 6 Hadden (2018)

Capsid id C Colle ollective M Mot otions 7 Hadden (2018)

Capsid distortio ion may ay b be a a func unctional featur ure Immature (pgRNA) Mature (dsDNA) Maturation 8 .

Solvent a and I d Ion n Excha hange Exchange Rates (ns -1 ) Water Sodium Chloride Inward 4700 8.4 1.8 Outward 4700 8.5 1.7 9 Hadden (2018)

Sodi dium t trans nslocate t through h triangul ular p r pores Δ G = -1.00 kcal/mol 10 Hadden (2018)

Capsid-di disru rupting d drug rugs HAP1 HAP18 AT130 11

Capsid M Morph rphology: S : Simul ulations ns v vs. E Experi riments Perilla, Hadden (2016) 12 Schlicksup, Zlotnick (2018)

Dr Drugs a alter r capsid m d morpho rphology Less spherical More faceted 13

Simulations f facilit itate i e inter erpret etation of exper erimen ents • Mutation introduces larger hydrophobic sidechain • Enhances capsid assembly • Increases drug resistance • But experimental structures do not explain these observations • Residue does not participate in subunit-subunit interaction • Residue is at the mouth of the drug binding pocket, not inside it 14

Simulations f facilit itate i e inter erpret etation of exper erimen ents 15 Ruan, Hadden, Zlotnick (2018)

Simulations r revea eal b l basis of of drug-bindin ing c cooper erativi vity % occupancy B C B C B C B C apo-capsid HAP-18 HAP-18 HAP-18 16 B C B and C

Capsid d dyna namics l limit cryo yo-EM EM r resolution 17 Hadden (2018)

Acknowledgements Professor Adam Zlotnick @ IU Dr. Balasubramanian Venkatakrishnan Christopher Schlicksup Lu Ruan Professor Klaus Schulten @ UIUC Dr. Boon Chong Goh Professor Juan R. Perilla @ UD Co-PI, Blue Waters Illinois Allocation 2017 PI, Blue Waters Broadening Participation Allocation 2018 PI, Blue Waters GLCPC Allocation 2019 18