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

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

Aug 11, 2023 18 likes •198 views

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

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The Hepatitis B Capsid through the Computational Microscope

Jodi A. Hadden University of Delaware Blue Waters Symposium 2019

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SLIDE 2

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

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SLIDE 3

A B C D

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12 vertices 20 faces 30 edges Surface proteins DNA Lipid membrane Capsid

Hep epatit itis is B B Vi Virus Capsid id

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SLIDE 4

Microsec econd s simula lation a at native e conditions

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Drug molecule

Parameterization

MD simulation of 6 M atoms for 1 μs without restraints Capsid subunit

Assemble using symmetry rules; Model in missing protein fragments

Native drug-bound capsid in 150 mM NaCl solvent box Drug molecule with force field parameters

Crystallography

Complete capsid 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

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SLIDE 5

Global C l Capsid F Flexib ibili lity

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Hadden (2018)

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SLIDE 6

Capsid A Asymmetry

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Hadden (2018)

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SLIDE 7

Capsid id C Colle

  • llective M

Mot

  • tions

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Hadden (2018)

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SLIDE 8

Capsid distortio ion may ay b be a a func unctional featur ure

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Immature (pgRNA) Mature (dsDNA) Maturation

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SLIDE 9

Solvent a and I d Ion n Excha hange

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Hadden (2018) Water Sodium Chloride Inward 4700 8.4 1.8 Outward 4700 8.5 1.7

Exchange Rates (ns-1)

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Sodi dium t trans nslocate t through h triangul ular p r pores

ΔG = -1.00 kcal/mol

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Hadden (2018)

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SLIDE 11

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HAP1 HAP18 AT130

Capsid-di disru rupting d drug rugs

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Capsid M Morph rphology: S : Simul ulations ns v

  • vs. E

Experi riments

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Perilla, Hadden (2016) Schlicksup, Zlotnick (2018)

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Dr Drugs a alter r capsid m d morpho rphology

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Less spherical More faceted

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  • 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

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Simulations f facilit itate i e inter erpret etation of exper erimen ents

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SLIDE 15

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Simulations f facilit itate i e inter erpret etation of exper erimen ents

Ruan, Hadden, Zlotnick (2018)

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Simulations r revea eal b l basis of

  • f drug-bindin

ing c cooper erativi vity

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% occupancy B C B C B C B C

apo-capsid HAP-18 B HAP-18 C HAP-18 B and C

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SLIDE 17

Capsid d dyna namics l limit cryo yo-EM EM r resolution

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Hadden (2018)

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SLIDE 18

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

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