Role of thumb index fold in Wnt-4 protein and its dynamics through a molecular dynamics simulation study

摘要

Wnt-4 is an important signaling protein of the Wnt family that acts in paracrinemanner to a few cell diameters. Wnt-4 takes part in many developmental processes including sex determination, and kidney development and also plays role in brain as well. Wnt-4 has a total of 25 cysteine residues with conserved locations in relation to whole Wnt family. Due to unchallenged importance of Wnts and to study their unusual fold, Wnt-4 was considered for simulation to interpret and extract structural features dynamically. Comparative modeling approach was utilized to model Wnt-4 and minimized to remove any energy restraints. The minimized model was then subjected to molecular dynamics simulation with periodic boundary conditions, to understand its behavior in the presence of water-box. Wnt-4 behavior for 20-nanosecond (ns) simulation was analyzed by calculating the root mean square deviation (RMSD), root mean square fluctuation (RMSF), and b-factor. Prominently, twenty (20) cysteine residues were observed in the edges of loops participating in interactions with frizzled receptors. The higher values of RMSD with comparison to higher values of RMSF and b-factor of residues accompanying 20 cysteine residues lying in regions nearer to N- and C-terminal domains extrapolate that these residuesmight be involved in cysteine-cysteine disulfide linkages and aremore important structurally and functionally as well.