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Hydropathy Patterning Complements Charge Patterning to Describe Conformational Preferences of Disordered Proteins.

ABSTRACT: Understanding the conformational ensemble of an intrinsically disordered protein (IDP) is of great interest due to its relevance to critical intracellular functions and diseases. It is now well established that the polymer scaling behavior can provide a great deal of information about the conformational properties as well as liquid-liquid phase separation of an IDP. It is, therefore, extremely desirable to be able to predict an IDP's scaling behavior from the protein sequence itself. The work in this direction so far has focused on highly charged proteins and how charge patterning can perturb their structural properties. As naturally occurring IDPs are composed of a significant fraction of uncharged amino acids, the rules based on charge content and patterning are only partially helpful in solving the problem. Here, we propose a new order parameter, sequence hydropathy decoration, which can provide a near-quantitative understanding of scaling and structural properties of IDPs devoid of charged residues. We combine this with a charge patterning parameter, sequence charge decoration, to obtain a general equation, parametrized from extensive coarse-grained simulation data, for predicting protein dimensions from the sequence. We finally test this equation against available experimental data and find a semiquantitative match in predicting the scaling behavior. We also provide guidance on how to extend this approach to experimental data, which should be feasible in the near future.

SUBMITTER: Zheng W

PROVIDER: S-EPMC7450210 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Prediction of protein folding and specific interactions from only the sequence (ab initio) is a major challenge in bioinformatics. It is believed that such prediction will prove possible if Anfinsen's thermodynamic principle is correct for all kinds of proteins, and all the information necessary to form a concrete 3D structure is indeed present in the sequence.We indexed the 200 possible amino acid pairs for their compatibility regarding the three major physicochemical properties--size, charge and hydrophobicity--and constructed Size, Charge and Hydropathy Compatibility Indices and Matrices (SCI & SCM, CCI & CCM, and HCI & HCM). Each index characterized the expected strength of interaction (compatibility) of two amino acids by numbers from 1 (not compatible) to 20 (highly compatible). We found statistically significant positive correlations between these indices and the propensity for amino acid co-locations in real protein structures (a sample containing total 34630 co-locations in 80 different protein structures): for HCI: p < 0.01, n = 400 in 10 subgroups; for SCI p < 1.3E-08, n = 400 in 10 subgroups; for CCI: p < 0.01, n = 175). Size compatibility between residues (well known to exist in nucleic acids) is a novel observation for proteins. Regression analyzes indicated at least 7 well distinguished clusters regarding size compatibility and 5 clusters of charge compatibility. We tried to predict or reconstruct simple 2D representations of 3D structures from the sequence using these matrices by applying a dot plot-like method. The location and pattern of the most compatible subsequences was very similar or identical when the three fundamentally different matrices were used, which indicates the consistency of physicochemical compatibility. However, it was not sufficient to choose one preferred configuration between the many possible predicted options.Indexing of amino acids for major physico-chemical properties is a powerful approach to understanding and assisting protein design. However, it is probably insufficient itself for complete ab initio structure prediction.

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Hydropathy Patterning Complements Charge Patterning to Describe Conformational Preferences of Disordered Proteins.

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