Animations

In animations developed by Mayo Clinic's Drug Discovery, Design and Optimization for Novel Therapeutics Laboratory, Dr. Caulfield's team demonstrates algorithms used for structural biology, drug design and large conformational changes needed to understand biological processes that are important for probing behavior.

Protein behavior

1. Uses simulations that include both long-standard runs and algorithms with enhanced sampling.
2. Generates conformations of the enzyme, protein or complex that may not be available from static X-ray structure or other data sources, such as nuclear magnetic resonance (NMR) and cryogenic electron microscopy (cryo-EM).
3. Visualizes dynamics changes of structures to reveal insights into protein function and behavior. Can newly identified structures be targeted using above methods?
4. Leads, potentially, to new ideas on how to modulate the protein or enzyme behavior. For example, can the lab team determine the genetic variant's intrinsic function as benign or pathogenic? Can we target this variant using above methods?
5. Allows Maxwell's demon molecular dynamics (MdMD) algorithm to capture rare and hard-to-reach states for studying.

Small Molecule Therapeutics Program (virtual to actual screening)

1. Discovery Phase 1; Hit Identification Phase 2; Hit Validation to establish structure-activity relationships.
2. Design Implementation (parallel to sister analogs), such as scanning around chem-space for 3D quantitative structure-activity relationship (3D-QSAR) and potential pharmacophores for new classes of lead compounds.
3. Analyze the generated de novo drugs and continue to optimize these candidate drugs, which generates intellectual property when the results have high potency and efficacy.
4. Quantum docking allows us to focus in on top leads for final modifications. See Quantum Docking animation.

Protein-protein modeling (biologics)

1. Categorized as a kind of docking technique, which we can use MdMD for as well.
2. Useful for determining protein-protein interfaces, such as ubiquitin ligase Parkin or PTEN-induced putative kinase protein 1 (PINK1). See Parkin MdMD animation.
3. Can help generate mutagenesis predictions for actual bench-top testing, thereby reducing cost and amount of required bench tests needed to get same or better result. Speed is key!
4. This can be a precursor to a small molecule screening campaign or to a biologics approach or to better understand protein engineering. See Mesotrypsin-APPI Dynamics animation.