Emmanuelle Bignon
Danish Cancer Society, Denmark
Title: Towards an accurate description of the S-nitrosylated cysteine by classical molecular simulations: implications for the study of cancer related SNO-proteins
Biography
Biography: Emmanuelle Bignon
Abstract
Nitric oxide plays an important role in the redox signaling pathway. Indeed, its reaction with cysteines, resulting in the
formation of S-nitrosothiols, has shown to be involved in a broad variety of biochemical and physiological processes in a
large variety of organisms. Large amounts of investigations have been led in order to understand the regulation mechanisms
driven by protein S-nitrosylation and their implications in cancer cells development. Th ousands of proteins have been proven
to undergo S-nitrosylation in vivo and the dysregulation of this process is implicated in various types of severe diseases,
including cancer onset, progression and treatment resistance. Th us, the understanding of S- nitrosylated proteins (SNOproteins)
structural behavior and reactivity is of utmost importance towards the development of new anti-cancer therapeutics.
Nowadays, there is a lack of information concerning the structural and electronic features of nitrosylated cysteine, with only few
NMR and x-ray structures reported for SNO proteins. In this framework, molecular modeling has been proven to be a useful
tool to obtain predictive structural and dynamical behavior of biomolecules. Th e S-nitrosocysteine (CysNO) non-canonical
amino acid exhibits a very complex chemistry, due to the presence of two antagonist resonance structures with very diff erent
electronic features. Th erefore, the accurate description of this moiety’s structure is highly challenging, and prediction of its
chemical properties has to be performed using high-level quantum methods. Unfortunately, such methods are strongly timeconsuming,
and their computational cost is prohibitive for the study of large system such as proteins. Force fi eld parameters
have been developed in order to perform classical molecular dynamics simulations of S-nitrosylated proteins to decipher their
dynamical features. Nevertheless, the accuracy of these parameters has not been extensively cross-validated and still need to be
tested. For this purpose, we performed extensive all-atom classical molecular dynamics simulations on proteins for which the
crystal structures harboring CysNO have been reported. Th e conformations sampled by all atom simulations with the two sets
of parameters have been confronted to the experimental structures in order to validate their effi ciency in reproducing CysNO
behavior. Th is checking is an important step in the design of accurate force fi eld parameters, which would allow computational
chemist to investigate the dynamical properties of S-nitrosylated proteins and their involvement in cancer cells mechanisms.