Development of Original BCL2-Venetoclax Bound Structures for Use in Molecular Dynamic Simulations

Helen Ashdown

Mentor: Dr. Matthew  McCoy, Innovation Center for Biomedical Informatics (ICBI), Department of Oncology, Georgetown University Medical Center.

Date/Time: August 24, 2021 at 1:20pm

Abstract: Molecular dynamics (MD) is a type of computer simulation used to study the movement of atoms and molecules within a biological system. When studying protein structures, the simulated dynamics of these molecules allow for the visualization of protein domains and insight into their functionalities. MD simulations can be used when understanding somatic variation in the protein targets of small molecule drug therapies, like the cancer therapy drug Ventoclax (LBM) and its target protein, BCL2. BLC2 belongs to a family of pro-survival proteins which bind to and restrain pro-apoptotic proteins, rendering them unable to function in their ability to detect cellular stress and affect apoptosis regulation. Venetoclax is a BCL2-antagonist designed to target and block the binding groove which BLC2 proteins act upon. There are documented mutations in the BCL2 protein which have become resistant to Ventoclax by blocking the drugs binding site and thus evade the drug’s effects. 

MD simulations are a computational approach to studying these protein mutations and drug resistances and can be used to build a predictive model of variant induced drug resistance. However, to run MD simulations within NAMD (the free molecular dynamic simulation software of choice), the mathematical expression of the potentials which atoms experience must be defined. This is called a force field, and these potentials are what lead to molecular motion. For a simulation to run, every single atom in a system needs those potentials defined within a set of parameters. This force field parameter file did not exist for the venetoclax drug, nor the drug within the system. Once an original parameterization force field was constructed, MD simulations of the bound venetoclax-protein structure were run within NAMD. By creating the necessary input files for MD simulations of the drug, the WT structure, and two variants, the results of the MD simulations were used to study the energetics and dynamic conformational changes of the mutated drug-protein system. Initial MD simulations of the WT and variants show differences in their energetic equilibriums which were used to build a model of the Gibbs free energy of binding. Once validated, such a model would be a useful tool for predicting variant specific drug interactions and used to help plan personalized therapeutic strategies in BCL2 positive cancers.