Computational Prediction of ALS Patient Survival Times from Protein Mechanical Properties

Abstract

Superoxide dismutase-1 (SOD1) is a Cu and Zn binding, homodimeric free radical defense enzyme, whose misfolding and aggregation play a key role in amyotrophic lateral sclerosis (ALS), a presently incurable and invariably fatal neurodegenerative disease. Over 150 mutations in SOD1 have been identified with a familial form of the disease, but it is presently not clear what unifying features, if any, these mutants share to make them pathogenic. We have developed a new computational assay to answer this question. We probe the mechanical properties of ALS-associated SOD1 mutants by simulating a series of atomic force microscopy experiments with variable tether positions. Such assays would be currently difficult or impossible experimentally, but by harnessing the power of computer simulations to manipulate proteins in a virtual environment, mechanical force studies may be designed to directly address those processes critical to the propagation of misfolding and its role in disease. These studies enabled us to quantify a mechanical rigidity “fingerprint” characterizing a given SOD1 variant, and as well to measure the severity of a given mutation upon structural integrity, metal affinity, and dimer stability. All ALS-associated mutants studied showed reduced structural integrity, an increased tendency to lose either Cu or Zn, and an increased tendency to monomerize; such processes are suspected to be critical in the progression of ALS. Upon closer analysis, we found that these stability and metal affinity measurements showed a remarkable ability to predict the lifetime of an ALS patient once neurodegenerative symptoms have been diagnosed.