title: Influence of V54M mutation in giant muscle protein titin: a computational screening and molecular dynamics approach.
abstract: Recent genetic studies have revealed the impact of mutations in associated genes for cardiac sarcomere components leading to dilated cardiomyopathy (DCM). The cardiac sarcomere is composed of thick and thin filaments and a giant muscle protein known as titin or connectin. Titin interacts with T-cap/telethonin in the Z-line region and plays a vital role in regulating sarcomere assembly. Initially, we screened all the variants associated with giant protein titin and analyzed their impact with the aid of pathogenicity and stability prediction methods. V54M mutation found in the hydrophobic core region of the protein associated with abnormal clinical phenotype leads to DCM was selected for further analysis. To address this issue, we mapped the deleterious mutant V54M, modeled the mutant protein complex, and deciphered the impact of mutation on binding with its partner telethonin in the titin crystal structure of PDB ID: 1YA5 with the aid of docking analysis. Furthermore, two run molecular dynamics simulation was initiated to understand the mechanistic action of V54M mutation in altering the protein structure, dynamics, and stability. According to the results obtained from the repeated 50 ns trajectory files, the overall effect of V54M mutation was destabilizing and transition of bend to coil in the secondary structure was observed. Furthermore, MMPBSA elucidated that V54M found in the Z-line region of titin decreases the binding affinity of titin to Z-line proteins T-cap/telethonin thereby hindering the protein-protein interaction.
authors.affiliation: a School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.
authors.forename: D
authors.initials: D
authors.lastname: Thirumal Kumar
authors.affiliation: a School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.
authors.forename: C
authors.initials: C
authors.lastname: George Priya Doss
authors.affiliation: a School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.
authors.forename: P
authors.initials: P
authors.lastname: Sneha
authors.affiliation: a School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.|b Faculty of Computing and Information Technology , King Abdulaziz University , Rabigh 21911 , Saudi Arabia.
authors.forename: Iftikhar Aslam
authors.initials: IA
authors.lastname: Tayubi
authors.affiliation: a School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.
authors.forename: R
authors.initials: R
authors.lastname: Siva
authors.affiliation: c Department of Bio-informatics , School of Computer and Information Sciences, Galgotias University , Greater Noida , Uttar Pradesh 201306 , India.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: d Faculty of Biomedical Sciences, Technology & Research, Department of Biotechnology , Sri Ramachandra University , Chennai , Tamil Nadu 600116 , India.
authors.forename: R
authors.initials: R
authors.lastname: Magesh
mesh_terms: D001665:Binding Sites; D003062:Codon; D003198:Computer Simulation; D064211:Connectin / Q000737:chemistry* / Q000235:genetics*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D003062:Codon; D064211:Connectin
keywords: MMPBSA; molecular docking and dynamics; nsSNP; titin; titin–telethonin