PT - JOURNAL ARTICLE AU - James P. Roney AU - Sergey Ovchinnikov TI - State-of-the-art estimation of protein model accuracy using AlphaFold AID - 10.1101/2022.03.11.484043 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.03.11.484043 4099 - http://biorxiv.org/content/early/2022/06/19/2022.03.11.484043.short 4100 - http://biorxiv.org/content/early/2022/06/19/2022.03.11.484043.full AB - The problem of predicting a protein’s 3D structure from its primary amino acid sequence is a longstanding challenge in structural biology. Recently, approaches like AlphaFold have achieved remarkable performance on this task by combining deep learning techniques with coevolutionary data from multiple sequence alignments of related protein sequences. The use of coevolutionary information is critical to these models’ accuracy, and without it their predictive performance drops considerably. In living cells, however, the 3D structure of a protein is fully determined by its primary sequence and the biophysical laws that cause it to fold into a low-energy configuration. Thus, it should be possible to predict a protein’s structure from only its primary sequence by learning a highly-accurate biophysical energy function. We provide evidence that AlphaFold has learned such an energy function, and uses coevolution data to solve the global search problem of finding a low-energy conformation. We demonstrate that AlphaFold’s learned potential function can be used to rank the quality of candidate protein structures with state-of-the-art accuracy, without using any coevolution data. Finally, we explore several applications of this potential function, including the prediction of protein structures without MSAs.Competing Interest StatementThe authors have declared no competing interest.