Resolving D-Amino Acid Containing Peptides Using Ion Mobility-Mass Spectrometry: Challenges and Recent Developments

Peptides and proteins having D-amino acids in their sequences are now believed to be widespread among different living organisms. Their significance is attributed to the diverse functions of these molecules, such as having a certain pathological implication or enhancing biological activity. Indeed, some peptide molecules with D-amino acids in their structure have already found their way to clinical use such as the antibacterial gramicidin and the antidiabetic nateglinide. Ion mobility mass spectrometry (IM-MS) added an additional dimension of separation as it depends on ions mobility in the space, which is dependent on their shapes, and the shape depends on the orientation of atoms. Thus, D-amino acids containing peptides (DAACPs) will have different mobility and collision cross-section values than those with L-amino acids. Eventually, this will lead to baseline separation of the two peptides. Additionally, ion mobility can precisely locate the position of D-amino acids by analyzing the difference in the arrival times of the fragment ions. The importance of DAACPs, as well as the difficulties in discovering them, were addressed in this review. Similarly, we emphasized how recent developments in IM-MS have improved their detection and analysis. Consequently, the LC-IM-MS/MS platform appears to be promising in isomeric mixture analysis.