Ruchi’s paper “Sequence Specificity Despite Intrinsic Disorder : How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein” is now submitted, and also available on ChemRxiv. This paper focuses on a mutation in the prodomain of Brain-derived Neurotrophic Factor (BDNF), which is associated with a range of stress-related disorders and neurodegeneration. The mutation can have dramatic effects on axon growth, but it’s such a seemingly subtle mutation (one amino acid is mutated to a similar amino acid, in a dynamic and disordered protein containing almost 100 amino acids), it’s surprising there are any detectable effects. The goal of this paper was to figure out the origin of these differences, so that we can improve our ability to predict which mutations of disordered proteins will actually affect protein function.
These simulations were done with atomistic resolution in explicit water, and took over 30 million hours of CPU time generously allocated by the Rutgers Discovery and Informatics Institute on the supercomputer Caliburn. One of the most interesting parts for us: to extract useful information from this large amount of generated data, we had to conceptualize (“see”) the protein in an entirely different way.