Biology subjects

Bronstein, A. M.

Publications and source records attributed to Bronstein, A. M..

4 recordsLinked to original sources

bioRxiv2024

The end of protein structure prediction: Improving prediction accuracy in chimeric proteins by windowed multiple sequence alignment

AlphaFold2 has predicted the structures of almost every known protein. A simple means to create proteins beyond those found in nature, is by unnaturally fusing together two known proteins. Here we demonstrate that dependence on multiple sequence alignment, limits the success with which AlphaFold and ESMfold capture such chimeric forms of otherwise well predicted, individual, proteins. Specifically we show that peptides are predicted with significantly reduced accuracy when added to the terminal ends of scaffold proteins. Appending the multiple sequence alignment for the individual peptide tags to that of the scaffold protein often restores prediction accuracy.

bioinformatics↗

bioRxiv2024

Seeing Double: Molecular dynamics simulations reveal the stability of certain alternate protein conformations in crystal structures

Proteins jiggle around, adopting ensembles of interchanging conformations. Here we show through a large-scale analysis of the Protein Data Bank and using molecular dynamics simulations, that segments of protein chains can also commonly adopt dual, transiently stable conformations which is not explained by direct interactions. Our analysis highlights how alternate conformations can be maintained as non-interchanging, separated states intrinsic to the protein chain, namely through steric barriers or the adoption of transient secondary structure elements. We further demonstrate that despite the commonality of the phenomenon, current structural ensemble prediction methods fail to capture these bimodal distributions of conformations.

biochemistry↗

bioRxiv2023

Water stabilizes an alternate turn conformation in horse heart myoglobin

Comparison of myoglobin structures reveals that protein isolated from horse heart consistently adopts an alternate turn conformation in comparison to its homologues. Analysis of hundreds of high-resolution structures discounts crystallization conditions or the surrounding amino acid protein environment as explaining this difference, that is also not captured by the AlphaFold prediction. Rather, a water molecule is identified as stabilizing the conformation in the horse heart structure, which immediately reverts to the whale conformation in molecular dynamics simulations excluding that structural water.

cell biology↗

bioRxiv2022

Defining amino acid pairs as structural units suggests mutation sensitivity toadjacent residues

Proteins fold from chains of amino acids, forming secondary structures, -helices and {beta}-strands, that, at least for globular proteins, subsequently fold into a three-dimensional structure. A large-scale analysis of high-resolution protein structures suggests that amino acid pairs constitute another layer of ordered structure, more local than these conventionally defined secondary structures. We develop a cross-peptide-bond Ramachandran plot that captures the conformational preferences of the amino acid pairs and show that the effect of a particular mutation on the stability of a protein depends in a predictable manner on the adjacent amino acid context. One-Sentence SummaryLarge-scale protein backbone analysis reveals amino acid pair conformational preferences and predicts how sequence context affects mutant stability.

molecular biology↗