Evolution of Mass Spectrometers for High <i>m</i>/<i>z</i> Biological Ion Formation, Transmission, Analysis and Detection: A Personal Perspective

Mass spectrometry (MS) has become an essential tool in virtually all academic, pharmaceutical, and biopharmaceutical analytical laboratories. The specialized and bespoke area of MS research and application of high <i>m</i>/<i>z</i> ion (><i>m</i>/<i>z</i> 6000 and high mass, >150 kDa) formation, transmission, analysis, and detection is a relatively new area of focus for MS that has seen dramatic acceleration in interest over the last two decades. Herein we delve into this exciting aspect of MS, discussing how MS instrumentation has been refined and evolved for native-MS analysis. We cover the early groundbreaking experiments showing high <i>m</i>/<i>z</i> ion formation, transmission, and preservation of protein structure in the gas phase. Additionally, we discuss specific instrument optimizations and modifications that have advanced high <i>m</i>/<i>z</i> ion generation, transmission, analysis, and detection, contributing to the research area known as gas-phase structural biology. Native-MS sample introduction methods, emerging technologies, and future perspectives are also examined. Finally, we share personal opinions, observations, and experiences that are new to the community or previously unpublished.