Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and always fatal disease that is associated with the selective death of upper and lower motor neurons, and for which the molecular basis of disease causation by mutations identified in affected individuals is still poorly understood. A large proportion of ALS is associated with mutations of genes that code for RNA-binding proteins, and notably mutations in the gene that codes for FUS (Fused in Sarcoma), a highly multifunctional protein that participates in RNA biology and metabolic processes that is highly characterized by its intrinsically disordered regions. As part of this dissertation research, the structural and functional implications of three different mutations associated with ALS in the FUS protein (G156E, R234L, and R521C) that map to distinct functional regions of the protein were analyzed by a computational scheme that integrates structure prediction by AlphaFold, calculation of intrinsic plasticity and binding plasticity by FuzPred, and molecular modeling simulations by HADDOCK to study crucial protein-protein and protein-RNA interactions. These studies clearly show that, while there is no large structural change in the overall protein structure, each of the mutations causes a site-directed and functionally relevant alteration in conformational dynamics and protein-binding properties. In particular, the R521C mutation enhances the difference in binding affinity between the FUS NLS and Transportin-1, indicating that there may be a mechanistic cause for impaired transport, whereas the G156E mutation destabilizes FUS-RNA binding, indicating that there may be a change in RNA-binding affinity. In sum, these data confirm that ALS-causing mutations in FUS cause disease primarily as a result of subtle changes in intrinsic disorder, binding versatility, or molecular recognition, as opposed to classical protein misfolding, and that structural biology predictions have provided insights that have helped to further our understanding of ALS.