Proteins are essential to life, supporting practically all its functions. They are large complex molecules, made up of chains of amino acids, and what a protein does largely depends on its unique 3D structure. Figuring out what shapes proteins fold into is known as the “protein folding problem”, and has stood as a grand challenge in biology for the past 50 years. In a major scientific advance, the latest version of our AI system AlphaFold has been recognised as a solution to this grand challenge by the organisers of the biennial Critical Assessment of protein Structure Prediction (CASP). This breakthrough demonstrates the impact AI can have on scientific discovery and its potential to dramatically accelerate progress in some of the most fundamental fields that explain and shape our world.
A protein’s shape is closely linked with its function, and the ability to predict this structure unlocks a greater understanding of what it does and how it works. Many of the world’s greatest challenges, like developing treatments for diseases or finding enzymes that break down industrial waste, are fundamentally tied to proteins and the role they play.
This has been a focus of intensive scientific research for many years, using a variety of experimental techniques to examine and determine protein structures, such as nuclear magnetic resonance and X-ray crystallography. These techniques, as well as newer methods like cryo-electron microscopy, depend on extensive trial and error, which can take years of painstaking and laborious work per structure, and require the use of multi-million dollar specialised equipment.
The ‘protein folding problem’
In his acceptance speech for the 1972 Nobel Prize in Chemistry, Christian Anfinsen famously postulated that, in theory, a protein’s amino acid sequence should fully determine its structure. This hypothesis sparked a five decade quest to be able to computationally predict a protein’s 3D structure based solely on its 1D amino acid sequence as a complementary alternative to these expensive and time consuming experimental methods. A major challenge, however, is that the number of ways a protein could theoretically fold before settling into its final 3D structure is astronomical. In 1969 Cyrus Levinthal noted that it would take longer than the age of the known universe to enumerate all possible configurations of a typical protein by brute force calculation – Levinthal estimated 10^300 possible conformations for a typical protein. Yet in nature, proteins fold spontaneously, some within milliseconds – a dichotomy sometimes referred to as Levinthal’s paradox.
In 1994, Professor John Moult and Professor Krzysztof Fidelis founded CASP as a biennial blind assessment to catalyse research, monitor progress, and establish the state of the art in protein structure prediction. It is both the gold standard for assessing predictive techniques and a unique global community built on shared endeavour. Crucially, CASP chooses protein structures that have only very recently been experimentally determined (some were still awaiting determination at the time of the assessment) to be targets for teams to test their structure prediction methods against; they are not published in advance. Participants must blindly predict the structure of the proteins, and these predictions are subsequently compared to the ground truth experimental data when they become available. We’re indebted to CASP’s organisers and the whole community, not least the experimentalists whose structures enable this kind of rigorous assessment.
The main metric used by CASP to measure the accuracy of predictions is the Global Distance Test (GDT) which ranges from 0-100. In simple terms, GDT can be approximately thought of as the percentage of amino acid residues (beads in the protein chain) within a threshold distance from the correct position. According to Professor Moult, a score of around 90 GDT is informally considered to be competitive with results obtained from experimental methods.
In the results from the 14th CASP assessment, our latest AlphaFold system achieves a median score of 92.4 GDT overall across all targets. This means that our predictions have an average error (RMSD) of approximately 1.6 Angstroms, which is comparable to the width of an atom (or 0.1 of a nanometer). Even for the very hardest protein targets, those in the most challenging free-modelling category, AlphaFold achieves a median score of 87.0 GDT.
These exciting results open up the potential for biologists to use computational structure prediction as a core tool in scientific research. Our methods may prove especially helpful for important classes of proteins, such as membrane proteins, that are very difficult to crystallise and therefore challenging to experimentally determine.