computational-chemistry

Yersinia pestis, the bacterium that causes the bubonic plague, uses a type III secretion system (T3SS) to inject toxins into host cells. The structure of the Y. pestis T3SS needle has not been modeled using AI or cryo-EM. T3SS in homologous bacteria have been solved using cryo-EM. Previously, we created possible hexamers of the Y. pestis T3SS needle protein, YscF, using CollabFold and AlphaFold2 Colab on Google Colab in an effort to understand more about the needle structure and calcium regulation of secretion. Hexamers and mutated hexamers were designed using data from a wet lab experiment by Torruellas et. al (2005). T3SS structures in homologous organisms show a 22 or 23mer structure where the rings of hexamers interlocked in layers. When folding was attempted with more than six monomers, we observed larger single rings of monomers. This revealed the inaccuracies of these online systems. To create a more accurate complete needle structure, a different computer software capable of creating a helical polymerized needle is required. The number of atoms in the predicted final needle is very high and more than our computational infrastructure can handle. For that reason, we need the computational resources of a supercomputer. We have hypothesized two ways to direct the folding that have the potential to result in a more accurate needle structure. The first option involves fusing the current hexamer structure into one protein chain, so that the software recognizes the hexamer as one protein. This will make it easier to connect multiple hexamers together. Alternatively, or additionally the cryo-EM structures of the T3SS of Shigella flexneri and Salmonella enterica Typhimurium can be used as models to guide the construction of the Y. pestis T3SS needle. The full AlphaFold library or a program like RoseTTAFold could help us predict protein-protein interactions more accurately for large structures. Based on our needs we have identified the TAMU ACES, Rockfish and Stampede-2 as promising resources for this project. The generated model of the Y. pestis T3SS YscF needle will provide insight into a possible structure of the needle. 

• Summary and objectives of the proposed experiments: 

1. An initial research-based Ab (scFv47, discovered by our collaborator Dr. Balyasnikova) model, modeling Ab-Ag (IL13RA2 against GBM) protein complex, and identifying the binding sites (epitopes) using ROSETTA and AlphaFold2 multimer tools.
2. Graft the CDRs of scFv (single-chain variable fragment) of antibody or Bispecific T cell engagers (BTEs) onto the template Ab, the framework of Lilly's Kisunla™ Ab drug.
3. Modify, improve, and optimize the overall or full antibody protein structures using AI-driven macromolecule modeling (AlphaFold3).
4. Explore single nucleotide polymorphism (SNP), pathogenic genetic variants and N-glycosylation of IL13RA2 (target) protein domain interacting with the Ab candidates among the patient population using ROSETTA software packages.

Solid metal hydrides are an attractive candidates for hydrogen storage materials. Magnesium has the benefit of being inexpensive, abundant, and non-toxic. However, the application of magnesium hydrides is limited by the hydrogen sorption kinetics. Doping magnesium hydrides with transition metal atoms improves this downfall, but much is still unknown about the process or the best choice of dopant type and concentration.

In this position, the student will study magnesium hydride clusters doped with early transition metals (e.g., Ti and V) as model systems for real world hydrogen storage materials.  Specifically, we will search each cluster's potential energy surface for local and global minima and explore the relationship of cluster size and dopant concentration on different properties.  The results from this investigation will then be compared with related cluster systems.

The student will begin by performing a literature search for this system, which will allow the student to pick an appropriate level of theory to conduct this investigation.  This level will be chosen by performing calculations on the MgM, MgH, and MH (M = Ti and V) diatomic species (and select other sizes based on the results of the literature search) and comparing the predictions with experimentally determined spectroscopic data (e.g., bond length, stretching frequency, etc.).  The student will then perform theoretical chemistry calculations using the Gaussian 16 and NBO 7 programs on the EXPANSE cluster housed at the San Diego Supercomputing Center (SDSC) through ACCESS allocation CHE-130094.  First, this student will generate candidate structures for each cluster size and composition using two global optimization procedures.  One program utilizes the artificial bee colony algorithm, whereas the second basin hoping program is written and compiled in-house using Fortran code. Additional structures will be generated by hand from our prior knowledge.  All candidate structures will then be further optimized by the student at the appropriate level determined at the start of the semester.  Higher level (e.g., double hybrid density functional theory) calculations will also be performed as further confirmation of the predicted results. Various results will be visualized with the Avogadro, Gabedit, and Gaussview programs on local machines.