Uncovering the functional effects of biomolecular mutations through computer simulations

Peter Huwe, University of Pennsylvania


Amino acid substitutions, or mutations, in proteins have been implicated in a host of human diseases. Protein mutations are heterogeneous in nature. Some mutations hamper protein function, while others may induce hyperactivity in the protein, and still others may leave the protein's activity relatively unaffected. Uncovering the functional effects of individual mutations is vital to understanding disease etiology, to engineering biomolecules to optimize function, and developing therapeutic agents. Using computer simulations in conjunction with, or in lieu of, traditional wet lab experiments may reveal the phenotype of mutations and provide insight into molecular mechanisms underlying changes in protein activity. In this work, we employ molecular modeling and computer simulations to (1) understand how Activation-Induced Cytidine Deaminase (AID) activity can be optimized through selective mutations; (2) describe how polymorphisms in Mitochondrial Transcription Factor A (TFAM) affect protein stability and DNA binding; (3) predict whether Anaplastic Lymphoma Kinase (ALK) mutations identified neuroblastoma patients constitutively activate the protein and drive progression of the disease. Our results effectively recapitulate and provide molecular context to experimental results while also demonstrating the potential for future use of simulations in clinical diagnostics.

Subject Area

Molecular biology|Biochemistry|Biophysics

Recommended Citation

Huwe, Peter, "Uncovering the functional effects of biomolecular mutations through computer simulations" (2014). Dissertations available from ProQuest. AAI3635511.