Local Hydration Control and Functional Implications Through S-Nitrosylation of Proteins: Kirsten rat sarcoma virus (KRAS) and Hemoglobin (Hb)

TL;DR

This study uses molecular dynamics simulations to analyze how S-nitrosylation affects the structure, hydration, and dynamics of KRAS and Hemoglobin proteins, revealing functional implications and challenges in experimental detection.

Contribution

It provides detailed molecular insights into the effects of S-nitrosylation on specific proteins, highlighting structural and hydration changes with potential functional consequences.

Findings

KRAS S-nitrosylation rigidifies the Switch-I region.

Hemoglobin nitrosylation increases secondary structure flexibility.

Hydration access decreases by 40% after nitrosylation.

Abstract

S-nitrosylation, the covalent addition of NO to the thiol side chain of cysteine, is an important post-transitional modification (PTM) that can affect the function of proteins. As such, PTMs extend and diversify protein functions and thus characterizing consequences of PTM at a molecular level is of great interest. Although PTMs can be detected through various direct/indirect methods, they lack the capabilities to investigate the modifications at the molecular level. In the present work local and global structural dynamics, their correlation, the hydration structure, and the infrared spectroscopy for WT and S-nitrosylated Kirsten rat sarcoma virus (KRAS) and Hemoglobin (Hb) are characterized from molecular dynamics simulations. It is found that for KRAS attaching NO to Cys118 rigidifies the protein in the Switch-I region which has functional implications, whereas for Hb nitrosylation at Cys93 at the $\beta_1$ chain increases the flexibility of secondary structural motives for Hb in its T$_{0}$ and R$_{4}$ conformational substates. Solvent water access decreased by 40\% after nitrosylation in KRAS, similar to Hb for which, however, local hydration of the R$_4$NO state is yet lower than for T$_0$NO. Finally, S-nitrosylation leads to detectable peaks for NO stretch, however, congested IR region will make experimental detection of these bands difficult.