Notes on Macromolecular Crystallography from the Turn of the Century

Abstract

I started these notes in the mid-1980s when I taught an informal course on the foundations of macromolecular crystallography for interested students and postdocs at UCLA. They were not intended as a comprehensive and systematic overview of crystallography, but rather as an introduction to some of the more mysterious or challenging aspects encountered in these studies that were of particular interest to me at that time – specifically, the relationship between X-ray scattering and structure, how to find heavy atoms and calculate phases, how to identify any non-crystallography symmetry operators, and how to refine an initial set of parameters. Phasing was generally the rate determining step in that era and so these activities naturally occupied a significant amount of the crystallographer’s time (along with preparing suitable crystals in the first place). The foundational material discussed in these notes was motivated by problems that arose in our research and the examples used to illustrate various topics were often based on these experiences. I am the first to acknowledge that many important topics, including data collection, data processing, model building and model refinement, are not discussed in the depth they merit, primarily because I was unable to improve upon the available programs and so I focused my efforts on phasing the projects under investigation in the group.

These notes reflect the state of macromolecular crystallography in the early 2000s. Beginning at that time, the availability of MAD phasing methods, increasing numbers of models for molecular replacement, superb synchrotron beamlines and remarkable software packages, revolutionized the practice of macromolecular crystallography. Consequently, the ability to solve heavy atom derivatives from Patterson maps was no longer a critical survival skill. The subsequent revolutions in cryo-electron microscopy and computation (i.e., AlphaFold) have completely transformed structural biology. Not coincidentally, the driving force in structural biology has largely changed from an emphasis on solving the “first” in a family of structures, to an emphasis on the “function” part of the structure-function paradigm exemplified from the earliest days of the field by Max Perutz. As a result of these developments, there is no longer any compelling need to update the material in these notes, particularly the references, and so they reflect the state of the macromolecular crystallography at the turn of the century.

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