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All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

https://doi.org/10.3390/v13040564

Pérez-Segura, Carolina ; Goh, Boon Chong ; Hadden-Perilla, Jodi A. ( April 2021 , Viruses)

The hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important antiviral paradigm based on disrupting the timing of genome packaging. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that the compound increases spike flexibility and improves recovery of helical secondary structure in the spike tips. Regions of the capsid-incorporated dimer that undergo correlated motion correspond to established sub-domains that pivot around the central chassis. AT130 alters patterns of correlated motion and other essential dynamics. A new conformational state of the dimer is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these sub-domains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.
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All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

https://doi.org/10.1021/acs.jpclett.6b00517

Perilla, Juan R. ; Hadden, Jodi A. ; Goh, Boon Chong ; Mayne, Christopher G. ; Schulten, Klaus ( May 2016 , The Journal of Physical Chemistry Letters)
Computational de novo design of antibodies binding to a peptide with high affinity

https://doi.org/10.1002/bit.26244

Poosarla, Venkata Giridhar ; Li, Tong ; Goh, Boon Chong ; Schulten, Klaus ; Wood, Thomas K. ; Maranas, Costas D. ( February 2017 , Biotechnology and Bioengineering)

ABSTRACT
Antibody drugs play a critical role in infectious diseases, cancer, autoimmune diseases, and inflammation. However, experimental methods for the generation of therapeutic antibodies such as using immunized mice or directed evolution remain time consuming and cannot target a specific antigen epitope. Here, we describe the application of a computational framework called OptMAVEn combined with molecular dynamics to de novo design antibodies. Our reference system is antibody 2D10, a single‐chain antibody (scFv) that recognizes the dodecapeptide DVFYPYPYASGS, a peptide mimic of mannose‐containing carbohydrates. Five de novo designed scFvs sharing less than 75% sequence similarity to all existing natural antibody sequences were generated using OptMAVEn and their binding to the dodecapeptide was experimentally characterized by biolayer interferometry and isothermal titration calorimetry. Among them, three scFvs show binding affinity to the dodecapeptide at the nM level. Critically, these de novo designed scFvs exhibit considerably diverse modeled binding modes with the dodecapeptide. The results demonstrate the potential of OptMAVEn for the de novo design of thermally and conformationally stable antibodies with high binding affinity to antigens and encourage the targeting of other antigen targets in the future. Biotechnol. Bioeng. 2017;114: 1331–1342. © 2017 Wiley Periodicals, Inc.

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