The Role of Molecular Simulation for Key Applications in Biotherapeutics

ABSTRACT

To design biotherapeutics, we must be able to predict and characterize their critical quality attributes, including structure, dynamics, and binding energies. When one considers the complexity of chemical space involved for modified nucleic acids, or the dynamics of very large antibodies, the expense in time and people-hours dramatically increases. To address the industry need for predictive models to streamline investigation, we have undertaken molecular dynamics simulations, which interface with experiments to advance biotherapeutic development. I will talk about protein and nucleic acid drugs, and the challenges in simulating each kind of molecule. I will detail the motivation behind using all-atom molecular dynamics, the results from rigorous validation against experiment, and the applications to several real-world examples.

BIOGRAPHY

Dr. Christina Bergonzo began her research career as an undergraduate at Manhattan College, studying transition state intermediates in cyclization reactions using high level quantum mechanics calculations. After graduating from Manhattan College with a Bachelor of Science in Chemistry, she went on to graduate school at Stony Brook University in Professor Carlos Simmerling’s Group. As a graduate student, she helped develop the partial Nudged Elastic Band method and, combined with molecular dynamics simulations, used it to study the mechanism of repairing oxidative damage to DNA. She earned her Ph.D. in Chemistry in 2012 and became a post-doctoral researcher with Professor Tom Cheatham at the University of Utah. There she helped implement the multi-dimensional replica exchange method in the Amber MD software package and used it to perform in-depth assessments of the current state of nucleic acid force fields, ultimately revealing the importance of water models in reproducing experimental results with MD simulations of nucleic acids. In 2017 she received an NRC post-doctoral fellowship from the National Academies of Sciences, Engineering and Medicine to work at NIST, and in 2021 became a Research Chemist in the Biomolecular Structure and Function Group at NIST/IBBR. Her current work focuses on developing improved computational simulation methods and integrating data from experimental methods to address NIST priority areas in biomanufacturing.