Molecular Modeling Facility

Research Inst Of Fox Chase Can Ctr, Philadelphia PA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT – SHARED RESOURCE: MOLECULAR MODELING FACILITY The goal of the Molecular Modeling Facility (MMF) is to provide FCCC members with structural information for proteins and protein complexes to enable the generation of mechanistic hypotheses in cancer biology, prevention, and therapeutic development. The MMF derives structural information from the Protein Data Bank (PDB) and the application of deep learning structure prediction methods such as DeepMind’s AlphaFold2 and AlphaFold-Multimer. The MMF identifies relevant experimental structures from bioinformatics tools developed in the Dunbrack lab and elsewhere. In the last two years, the accuracy of protein structure prediction has increased substantially. Previously molecular modeling relied on structure prediction by homology, which is dependent on the availability of experimental structures related to the target(s). Now, with AlphaFold2, it is possible for the MMF to predict the structures of the folded regions of almost all human proteins and those of relevant model organisms to near experimental accuracy. Even more important, AlphaFold-Multimer can predict structures of stable multi-protein complexes with high accuracy, guiding testable hypotheses on protein-protein interactions in cancer-relevant molecular pathways. In cancer genetics, the MMF utilizes experimental and computationally derived structures of proteins and proteins complexes to assist investigators in the interpretation of mutations observed in patient samples. As the field of deep-learning based structure prediction and protein design evolves, the MMF will continue to incorporate new methods in our computational pipelines and will develop high- throughput computational screening of protein-protein interactions and mutation assessments. The facility provided service to 18 FCCC members for the 12 months ending 10/31/23. Several of the projects required months of effort and comprised substantial portions of the relevant manuscripts. Table 2 further illustrates the number of peer reviewed users by services offered by the MMF. For the 12 months ending 10/31/23, 347 direct service hours (99% of the total hours billed) were performed for Peer-Review Funded FCCC members. The MMF was utilized by 30 FCCC Members and essential to all three Programs in 2019-2023 (through October). The MMF is advised by a dedicated Facility Advisory Committee (FAC) that meets annually. Recommendations from the FAC are directed to a governing Facility Parent Oversight Committee that advises Senior Leadership to ensure that the MMF continues to have the necessary resources to provide the highest quality services for FCCC members.