Can proteins be truly designed sans function?

doi:10.1126/science.abd4791

GSTDTAP > 气候变化

DOI	10.1126/science.abd4791
	Can proteins be truly designed sans function?
	Anna Peacock
	2020-09-04
发表期刊	Science
出版年	2020
英文摘要	Proteins come in a wide range of sizes, shapes, and folds and perform a broad range of functions. Investigations into how and why proteins fold from peptide sequences to yield a particular structure have continued for decades ([ 1 ][1]) and have inspired efforts to design proteins de novo—that is, to rationally design structured miniature protein folds from first principles. Ultimately, the goal is not merely to design specific folds but to create proteins that execute functions—ideally, functions beyond the repertoire found in nature. When the desired function involves binding of small molecules, as is the case in many applications, this requirement adds an additional level of complexity and challenge. On page 1227 of this issue, Polizzi and DeGrado ([ 2 ][2]) have developed a search algorithm, Convergent Motifs for Binding Sites (COMBS), by which ligand-selective binding proteins can be designed truly de novo, thereby providing a much-needed tool for advancing functional protein design. The de novo design of a truly artificial protein fold was first reported for TOP7, a 93–amino acid mixed α/β-fold ([ 3 ][3]). Since then, the de novo design of protein structure has made impressive progress through enhanced understanding, expansion of the experimentally validated structures in the Protein Data Bank, greater computing power, and affordable access to synthetic genes that allow for greater experimental validation. Artificial peptides have also been designed to assemble into previously unknown architectures, including α-helical barrels featuring accessible channels through their core ([ 4 ][4]), large spherical cages ([ 5 ][5]), and polyhedral shapes ([ 6 ][6]). More recently, the development of protein folding and design online computer games has even allowed citizen scientists to design previously unexplored protein folds ([ 7 ][7]). Protein function can be achieved by the actual structure, such as collagen, but more often by the binding of complex small-molecule ligands generating sensors, receptors, or catalysts. A cavity must be designed with a size and shape to serve as a complementary “lock” for the target ligand “key” that aligns the target for favorable interactions but does not interfere with proper folding. The common strategy of designing a structure and then introducing a function often comes at the expense of proper structural folding or stability and is often not successful. ![Figure][8] De novo protein design Polizzi and DeGrado developed a unit of local protein structure called a van der Mer (vdM) that links ligand group chemical functionality and main-chain backbone coordinates to help design ligand-binding proteins. GRAPHIC: N. DESAI/ SCIENCE A more appealing approach would be to simultaneously design structure and function de novo. Previously reported strategies tend to position the target ligand relative to the interacting atoms of the amino acid side chain ([ 8 ][9], [ 9 ][10]). This approach can generate a large number of structures to evaluate computationally, and can also lead to combinations of coordinates and ligand rotamers that are not actually observed experimentally. Generally, approaches to date do not initially achieve strong binding, and subsequent rounds of experimental validation and redesign are often required. Polizzi and DeGrado designed an artificial protein fold that shares no sequence homology to native proteins and also has a binding site selective for a complex small molecule—in this case, the blood-thinning drug apixaban (see the figure). They developed a new unit of protein structure, which they call a van der Mer (vdM), that directly maps ligand chemical group functionality (such as carbonyl, carboxylate, carboxamide, and amine) to peptide residue backbone coordinates. Crucially, vdMs are generated from close contact with the side chain, the main chain, or both. Ligand chemical-group locations relate to backbone coordinates and not side chains, so vdMs link directly to the protein fold. The vdMs were extracted from the experimentally determined structures deposited in the Protein Data Bank, and the incidence of the various vdMs across the Protein Data Bank was used to score them. Surprisingly, only a modest number of vdMs are highly prevalent, making it computationally attractive to adopt this approach. Binding sites were engineered into designed four-helix bundle folds that are structurally unrelated to factor Xa, for which apixaban is an inhibitor ([ 10 ][11]), and that do not generally bind to small molecules. The authors searched for combinations of vdMs (favoring those with higher scores) that could be superimposed onto protein backbone templates and that presented chemical groups that could be overlaid with those of the target ligand. Flexible backbone sequence design was used to build the remainder of the sequence. Finally, low-energy, well-packed designs were validated by ab initio folding of sequences to establish designs that retained uncollapsed and preorganized binding sites in the absence of the bound target ligand. No subsequent downstream redesign was needed to enhance structural stability, function, or ligand-binding activity. This accomplishment represents an important step forward for de novo functional protein design. To achieve the full potential of de novo protein design, simultaneous design of function is required. Unfolded proteins, or those with intended or accidental mutations, can be nonfunctional, whereas biology's successful and intended folds offer function. Given that the repertoire of biological function has evolved through select evolutionary pressures, designed proteins that achieve the same function are unlikely to offer substantial advantages, so new functionality beyond the scope of biology is the goal. Recent developments, including the simultaneous design of protein structure and ligand-binding site by Polizzi and DeGrado, will provide exciting opportunities in sensing, light capture and storage, diagnostics, therapeutics, and catalysis, among others. The protein design community is now poised to design functional proteins that can begin to address some of the most pressing challenges facing society today, including ones in energy, health care, and sustainability. New protein design algorithms need to be made accessible to the nonexpert user, in a similar way to the protein design online computer games ([ 7 ][7]), if researchers with new creative functions in mind are to realize the full potential of protein design. 1. [↵][12]1. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/293262
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Anna Peacock. Can proteins be truly designed sans function?[J]. Science,2020.
APA	Anna Peacock.(2020).Can proteins be truly designed sans function?.Science.
MLA	Anna Peacock."Can proteins be truly designed sans function?".Science (2020).