AlphaFold2 models indicate that protein sequence determines both structure and dynamics

Abstract

AlphaFold 2 (AF2) has placed Molecular Biology in a new era where we can visualize, analyze and interpret the structures and functions of all proteins solely from their primary sequences. We performed AF2 structure predictions for various protein systems, including globular proteins, a multi-domain protein, an intrinsically disordered protein (IDP), a randomized protein, two larger proteins (> 1000 AA), a heterodimer and a homodimer protein complex. Our results show that along with the three dimensional (3D) structures, AF2 also decodes protein sequences into residue flexibilities via both the predicted local distance difference test (pLDDT) scores of the models, and the predicted aligned error (PAE) maps. We show that PAE maps from AF2 are correlated with the distance variation (DV) matrices from molecular dynamics (MD) simulations, which reveals that the PAE maps can predict the dynamical nature of protein residues. Here, we introduce the AF2-scores, which are simply derived from pLDDT scores and are in the range of [0, 1]. We found that for most protein models, including large proteins and protein complexes, the AF2-scores are highly correlated with the root mean square fluctuations (RMSF) calculated from MD simulations. However, for an IDP and a randomized protein, the AF2-scores do not correlate with the RMSF from MD, especially for the IDP. Our results indicate that the protein structures predicted by AF2 also convey information of the residue flexibility, i.e., protein dynamics.

The Rad52 SSAP superfamily and new insight into homologous recombination

“…1 ) and set the inherent curvature of the filaments formed by multimerization; (iii) a second α-helix (α2, green) packs with α3; followed by (iv) a β-hairpin and (v) α-helix 1. Utilizing AlphaFold 14 , 15 for SSAP modelling revealed that not only are other RecT/Redβ SSAPs based on the same design but also members of the Erf group (Fig. 1b ), as previously anticipated 12 .…”

Intrinsic Disorder as a Natural Preservative: High Levels of Intrinsic Disorder in Proteins Found in the 2600-Year-Old Human Brain

“…In fact, the authors of this preprint indicated: “AlphaFold2 assigns high-confidence scores to about 60% of a set of 350 IDRs that have been reported to conditionally fold, suggesting that AlphaFold2 has learned to identify conditionally folded IDRs, which is unexpected, since IDRs were minimally represented in the training data” [ 54 ]. Therefore, in addition to be able to accurately identify ordered domains and IDRs [ 55 , 56 , 57 , 58 ], AlphaFold is capable of finding IDRs that conditionally fold [ 54 ].…”

Mutant structure of metabolic switch protein in complex with monomeric c-di-GMP reveals a potential mechanism of protein-mediated ligand dimerization

“…Interestingly, loop 7 and helix 9 have low (70 > pLDDT > 50) and very low (pLDDT < 50) scores. It has been shown that AF2 correlated with the root mean square fluctuations (RMSF) calculated from MD (Molecular Dynamics) simulations experiments 35 . Thus the low AF2 scores of SmbA wt , suggest flexibility of loop 7 in the absence of the c-di-GMP (Supplementary Fig.…”