Steric interactions determine side-chain conformations in protein cores

Caballero, Diego; Virrueta, Alejandro; O’Hern, Corey S.; Regan, Lynne

doi:10.1093/protein/gzw027

Cited by 14 publications

(20 citation statements)

References 33 publications

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“…In prior work, we demonstrated that one can repack the side‐chains of residues in protein cores using only hard‐sphere repulsive interactions in the context of a calibrated atomistic model . In this study, we investigate whether the same approach can predict the conformations of amino acid side‐chains at protein‐protein interfaces and in transmembrane proteins.…”

Section: Resultsmentioning

confidence: 99%

“…We have shown that steric interactions between the side‐chain of a residue and the rest of the protein are necessary to accurately predict the side‐chain dihedral angles of amino acid residues . However, to obtain a lower bound on the prediction accuracy of the hard‐sphere model, we also predicted the side‐chain conformations for each amino acid without the rest of the protein, that is, each residue modeled as a dipeptide mimetic (Figure ).…”

Section: Methodsmentioning

confidence: 99%

“…When we consider both intra‐ and inter‐residue atomic interactions, the hard‐sphere model is able to predict the specific side‐chain conformation of each of these amino acids in protein cores . We have shown that Met requires additional attractive interactions for the hard‐sphere model predictions to match the observed side‐chain dihedral angle distributions, and that only about 50% of Ser residues can be predicted using the hard‐sphere model alone . (We presume that the absence of hydrogen‐bonding interactions explains the limited prediction accuracy of Ser using the hard‐sphere model.…”

Section: Introductionmentioning

confidence: 96%

“…We showed that the hard‐sphere model, when applied to a dipeptide mimetic (Figure ), is able to predict the side‐chain dihedral angle distributions observed in natural proteins for most of the uncharged residues (for example, Ile, Leu, Val, Thr, Tyr, Trp, Phe, and Cys) . When we consider both intra‐ and inter‐residue atomic interactions, the hard‐sphere model is able to predict the specific side‐chain conformation of each of these amino acids in protein cores . We have shown that Met requires additional attractive interactions for the hard‐sphere model predictions to match the observed side‐chain dihedral angle distributions, and that only about 50% of Ser residues can be predicted using the hard‐sphere model alone .…”

Section: Introductionmentioning

confidence: 96%

“…Such predictability is the key metric of success in protein design. In prior work, we investigated the range and limits of the predictability of protein side‐chain conformations for uncharged amino acids, using a simple repulsive‐only hard‐sphere plus stereochemical constraint model . We showed that the hard‐sphere model, when applied to a dipeptide mimetic (Figure ), is able to predict the side‐chain dihedral angle distributions observed in natural proteins for most of the uncharged residues (for example, Ile, Leu, Val, Thr, Tyr, Trp, Phe, and Cys) .…”

Section: Introductionmentioning

confidence: 99%

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Comparing side chain packing in soluble proteins, protein‐protein interfaces, and transmembrane proteins

et al. 2018

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We compare side chain prediction and packing of core and non-core regions of soluble proteins, protein-protein interfaces, and transmembrane proteins. We first identified or created comparable databases of high-resolution crystal structures of these 3 protein classes. We show that the solvent-inaccessible cores of the 3 classes of proteins are equally densely packed. As a result, the side chains of core residues at protein-protein interfaces and in the membrane-exposed regions of transmembrane proteins can be predicted by the hard-sphere plus stereochemical constraint model with the same high prediction accuracies (>90%) as core residues in soluble proteins. We also find that for all 3 classes of proteins, as one moves away from the solvent-inaccessible core, the packing fraction decreases as the solvent accessibility increases. However, the side chain predictability remains high (80% within 30°) up to a relative solvent accessibility, rSASA≲0.3, for all 3 protein classes. Our results show that ≈40% of the interface regions in protein complexes are "core", that is, densely packed with side chain conformations that can be accurately predicted using the hard-sphere model. We propose packing fraction as a metric that can be used to distinguish real protein-protein interactions from designed, non-binding, decoys. Our results also show that cores of membrane proteins are the same as cores of soluble proteins. Thus, the computational methods we are developing for the analysis of the effect of hydrophobic core mutations in soluble proteins will be equally applicable to analyses of mutations in membrane proteins.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Comparing side chain packing in soluble proteins, protein‐protein interfaces, and transmembrane proteins

et al. 2018

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Functional Analysis of BARD1 Missense Variants on Homology‐Directed Repair in Ovarian and Breast Cancers

Li,

Chen,

Wang

et al. 2024

Molecular Carcinogenesis

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Women with germline BRCA1 mutations face an increased risk of developing breast and ovarian cancers. BARD1 (BRCA1 associated RING domain 1) is an essential heterodimeric partner of BRCA1, and mutations in BARD1 are also associated with these cancers. While BARD1 mutations are recognized for their cancer susceptibility, the exact roles of numerous BARD1 missense mutations remain unclear. In this study, we conducted functional assays to assess the homology‐directed DNA repair (HDR) activity of all BARD1 missense substitutions identified in 55 breast and ovarian cancer samples, using the real‐world data from the COSMIC and cBioPortal databases. Seven BARD1 variants (V85M, P187A, G491R, R565C, P669L, T719R, and Q730L) were confirmed to impair DNA damage repair. Furthermore, cells harboring these BARD1 variants exhibited increased sensitivity to the chemotherapeutic drugs, cisplatin, and olaparib, compared to cells expressing wild‐type BARD1. These findings collectively suggest that these seven missense BARD1 variants are likely pathogenic and may respond well to cisplatin‐olaparib combination therapy. This study not only enhances our understanding of BARD1's role in DNA damage repair but also offers valuable insights into predicting therapy responses in patients with specific BARD1 missense mutations.

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A threonine zipper that mediates protein–protein interactions: Structure and prediction

Treado

Levine

et al. 2018

Protein Science

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We present the structure of an engineered protein-protein interface between two beta barrel proteins, which is mediated by interactions between threonine (Thr) residues. This Thr zipper structure suggests that the protein interface is stabilized by close-packing of the Thr residues, with only one intermonomer hydrogen bond (H-bond) between two of the Thr residues. This Thr-rich interface provides a unique opportunity to study the behavior of Thr in the context of many other Thr residues. In previous work, we have shown that the side chain (χ ) dihedral angles of interface and core Thr residues can be predicted with high accuracy using a hard sphere plus stereochemical constraint (HS) model. Here, we demonstrate that in the Thr-rich local environment of the Thr zipper structure, we are able to predict the χ dihedral angles of most of the Thr residues. Some, however, are not well predicted by the HS model. We therefore employed explicitly solvated molecular dynamics (MD) simulations to further investigate the side chain conformations of these residues. The MD simulations illustrate the role that transient H-bonding to water, in combination with steric constraints, plays in determining the behavior of these Thr side chains. Broader Audience Statement: Protein-protein interactions are critical to life and the search for ways to disrupt adverse protein-protein interactions involved in disease is an ongoing area of drug discovery. We must better understand protein-protein interfaces, both to be able to disrupt existing ones and to engineer new ones for a variety of biotechnological applications. We have discovered and characterized an artificial Thr-rich protein-protein interface. This novel interface demonstrates a heretofore unknown property of Thr-rich surfaces: mediating protein-protein interactions.

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Steric interactions determine side-chain conformations in protein cores

Cited by 14 publications

References 33 publications

Comparing side chain packing in soluble proteins, protein‐protein interfaces, and transmembrane proteins

Comparing side chain packing in soluble proteins, protein‐protein interfaces, and transmembrane proteins

Functional Analysis of BARD1 Missense Variants on Homology‐Directed Repair in Ovarian and Breast Cancers

A threonine zipper that mediates protein–protein interactions: Structure and prediction

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