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Energy functions in de novo protein design: current challenges and future prospects.

ABSTRACT: In the past decade, a concerted effort to successfully capture specific tertiary packing interactions produced specific three-dimensional structures for many de novo designed proteins that are validated by nuclear magnetic resonance and/or X-ray crystallographic techniques. However, the success rate of computational design remains low. In this review, we provide an overview of experimentally validated, de novo designed proteins and compare four available programs, RosettaDesign, EGAD, Liang-Grishin, and RosettaDesign-SR, by assessing designed sequences computationally. Computational assessment includes the recovery of native sequences, the calculation of sizes of hydrophobic patches and total solvent-accessible surface area, and the prediction of structural properties such as intrinsic disorder, secondary structures, and three-dimensional structures. This computational assessment, together with a recent community-wide experiment in assessing scoring functions for interface design, suggests that the next-generation protein-design scoring function will come from the right balance of complementary interaction terms. Such balance may be found when more negative experimental data become available as part of a training set.

SUBMITTER: Li Z

PROVIDER: S-EPMC3851009 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Energy functions in de novo protein design: current challenges and future prospects.

Li Zhixiu Z Yang Yuedong Y Zhan Jian J Dai Liang L Zhou Yaoqi Y

Annual review of biophysics 20130228

In the past decade, a concerted effort to successfully capture specific tertiary packing interactions produced specific three-dimensional structures for many de novo designed proteins that are validated by nuclear magnetic resonance and/or X-ray crystallographic techniques. However, the success rate of computational design remains low. In this review, we provide an overview of experimentally validated, de novo designed proteins and compare four available programs, RosettaDesign, EGAD, Liang-Gris ...[more]

PMID: 23451890

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Project description:IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease.

Dataset Information

Energy functions in de novo protein design: current challenges and future prospects.

Publications

Energy functions in de novo protein design: current challenges and future prospects.

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