In silico analysis of PFN1 related to amyotrophic lateral sclerosis

Abstract

Profilin 1 (PFN1) protein plays key roles in neuronal growth and differentiation, membrane trafficking, and regulation of the actin cytoskeleton. Four natural variants of PFN1 were described as related to ALS, the most common adult-onset motor neuron disorder. However, the pathological mechanism of PFN1 in ALS is not yet completely understood. The goal of this work is to thoroughly analyze the effects of the ALS-related mutations on PFN1 structure and function using computational simulations. Here, PhD-SNP, PMUT, PolyPhen-2, SIFT, SNAP, SNPS&GO, SAAP, nsSNPAnalyzer, SNPeffect4.0 and I-Mutant2.0 were used to predict the functional and stability effects of PFN1 mutations. ConSurf was used for the evolutionary conservation analysis, and GROMACS was used to perform the MD simulations. The mutations C71G, M114T, and G118V, but not E117G, were predicted as deleterious by most of the functional prediction algorithms that were used. The stability prediction indicated that the ALS-related mutations could destabilize PFN1. The ConSurf analysis indicated that the mutation C71G, M114T, E117G, and G118V occur in highly conserved positions. The MD results indicated that the studied mutations could affect the PFN1 flexibility at the actin and PLP-binding domains, and consequently, their intermolecular interactions. It may be therefore related to the functional impairment of PFN1 upon C71G, M114T, E117G and G118V mutations, and their involvement in ALS development. We also developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented on this paper for biologists and clinicians to exploit PFN1 and its natural variants.