Section 25.1.1. Introduction

Since the pioneering work of Max Perutz and John Kendrew that yielded the structures of haemoglobin and myoglobin roughly forty years ago, macromolecular crystallography has become a cutting-edge research area of modern molecular biology. There has been a dramatic increase in the number of structures of biological macromolecules determined by X-ray crystallography in the past two decades. The number of new structures of proteins, nucleic acids and their complexes with substrates and/or inhibitors deposited with the Protein Data Bank has been expanding dramatically in the last few years. The complexity of these new structures is also increasing. Knowledge derived from these structural studies is growing at a continually accelerating pace, as is their applicability to diverse problems in science and medicine.

These increases have resulted in part from major advances in the instrumentation, analytical methods and recombinant expression techniques that support macromolecular crystallography, including the utilization of more brilliant light sources (synchrotron radiation), charge-coupled-device (CCD) detectors, cryocrystallography, multiwavelength anomalous dispersion (MAD) phasing analysis and selenomethionyl proteins. Dramatic enhancement of all aspects of structure determination, including the introduction of powerful computer hardware of increasing capacity and sophisticated computational software, has markedly reduced the time and resources required to determine new structures while increasing the quality and accuracy of the results. Program development has benefited not only from technological advances but also from the development of new theories and algorithms in macromolecular X-ray crystallography.

The burgeoning field of structural genomics is presenting additional opportunities, as well as challenges, for structural biologists. In the near future, the complete map of the human genome will be known, representing a milestone in our ability to describe the natural world. The opportunities provided by knowing the complete human genetic blueprint are myriad across many fields, including biology, chemistry, materials science and medicine. Scientists are seeking answers to a growing number of challenging biological questions and ultimately would like to have access to the complete catalogue of protein structures in living systems, as well as to comprehend protein-folding space. Although it is not currently feasible to determine the structure of every protein, it has been suggested that structure determination of about 10 000 properly chosen proteins should permit reliable modelling of three-dimensional structures for hundreds of thousands of other proteins. X-ray crystallography is likely to produce the majority of structures required to achieve such a goal. More powerful, high-throughput methods are needed to facilitate determination and analysis of the hoard of new structures that will emerge from this initiative.

This article presents a survey of the computational software used most frequently by protein X-ray crystallographers in the structure determination of proteins and nucleic acids. This is not intended to provide complete or comprehensive information about every program on each aspect of protein crystallography, nor is it intended to present a complete compilation of available programs (apologies to those whose programs were not included – this is not meant as a slight!). Also, in cases where programs or program systems are described in articles elsewhere in this volume, only minimal descriptions are given here. Brief annotations on some of the most popular or frequently used programs in the crystallographic community are provided. We have liberally pirated program descriptions from the program authors where possible.

We anticipate that parts of this chapter will become outdated rapidly, owing to the ceaseless evolution of new methods and proliferation of new programs. Among the most volatile information may be addresses for locating the programs on the internet; judicious use of search engines should facilitate the task of finding updated locations. The reader is also referred to http://www.iucr.org/sincris-top/logiciel/ , which contains a compilation of a broad range of programs and software systems in crystallography, structural biology and molecular biology.

The program summaries are grouped somewhat arbitrarily into the following categories: