Influence of the SNPs on the structural stability of CBS protein: Insight from molecular dynamics simulations

Abstract

Cystathionine β-synthase is an essential enzyme of the trans-sulfuration pathway that condenses serine with homocysteine to form cystathionine. Missense mutations in CBS are the major cause of inherited homocystinuria, and the detailed effect of disease associated amino acid substitutions on the structure and stability of human CBS is yet unknown. Here, we apply a unique approach in combining in silico tools and molecular dynamics simulation to provide structural and functional insight into the effect of SNP on the stability and activity of mutant CBS. In addition, principal component analysis and free energy landscape were used to predict the collective motions, thermodynamic stabilities and essential subspace relevant to CBS function. The obtained results indicate that C109R, E176K and D376N mutations have the diverse effect on dynamic behavior of CBS protein. We found that highly conserved D376N mutation, which is present in the active pocket, affects the protein folding mechanism. Our strategy may provide a way in near future to understand and study effects of functional nsSNPs and their role in causing homocystinuria.

Key words： CBS; in silico; molecular dynamics simulation; SNPs

Compliance with ethics guidelines

All authors have not any potential conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

The authors take this opportunity to thank the management of Vellore Institute of Technology and Sri Ramachandra University for providing the facilities and encouragement to carry out this work.

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