title: Unraveling the molecular effects of mutation L270P on Wiskkot-Aldrich syndrome protein: insights from molecular dynamics approach.
abstract: Missense mutation L270P disrupts the auto-inhibited state of "Wiskkot-Aldrich syndrome protein" (WASP), thereby constitutively activating the mutant structure, a key event for pathogenesis of X-linked neutropenia (XLN). In this study, we comprehensively deciphered the molecular feature of activated mutant structure by all atom molecular dynamics (MD) approach. MD analysis revealed that mutant structure exposed a wide variation in the spatial environment of atoms, resulting in enhanced residue flexibility. The increased flexibility of residues favored to decrease the number of intra-molecular hydrogen bonding interactions in mutant structure. The reduction of hydrogen bonds in the mutant structure resulted to disrupt the local folding of secondary structural elements that eventually affect the proper folding of mutants. The unfolded state of mutant structure established more number of inter-molecular hydrogen bonding interaction at interface level due to the conformational variability, thus mediated high binding affinity with its interacting partner, Cdc42.
authors.affiliation: a Bioinformatics Division, School of Biosciences and Technology , VIT University , Vellore 632 014 , Tamil Nadu , India.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Palaniappan
authors.affiliation: a Bioinformatics Division, School of Biosciences and Technology , VIT University , Vellore 632 014 , Tamil Nadu , India.
authors.forename: Sethumadhavan
authors.initials: S
authors.lastname: Rao
authors.affiliation: a Bioinformatics Division, School of Biosciences and Technology , VIT University , Vellore 632 014 , Tamil Nadu , India.
authors.forename: Rajasekaran
authors.initials: R
authors.lastname: Ramalingam
mesh_terms: D000595:Amino Acid Sequence; D016000:Cluster Analysis; D003062:Codon; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D055550:Protein Stability; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; D051316:Wiskott-Aldrich Syndrome Protein
keywords: WASP; XLN; flexibility; hydrogen bonds; molecular dynamics