自然界中的演化過程,，是不斷的適應(yīng)環(huán)境的變化,，在微妙的差異中，慢慢的發(fā)展出方向,，因此演化的變化確實(shí)存在,，但也需歷經(jīng)長久的變化，而一份由美國亞歷桑那州立大學(xué) (Arizona State University) 生物設(shè)計(jì)研究所(Biodesign Institute) John Chaput 博士所主導(dǎo)的研究計(jì)劃,，就在實(shí)驗(yàn)室中,，嘗試著模擬達(dá)爾文的演化論，設(shè)計(jì)出自然界中,，要?dú)v經(jīng)三十億年才能演化出來的蛋白質(zhì),。
據(jù)參與的科學(xué)家發(fā)表在最新一期 PLoS ONE期刊的論文顯示，研究這個(gè)題目的目的,，除了能夠回答許多蛋白質(zhì)演化的基本問題外，還希望能夠因著了解蛋白質(zhì)演化的關(guān)鍵,，設(shè)計(jì)出具有特殊功能,，現(xiàn)代未曾出現(xiàn)的蛋白質(zhì)，這樣的蛋白質(zhì),，不但具有生物產(chǎn)業(yè)上應(yīng)用的價(jià)值,，還可以開發(fā)新一代的藥物。
研究人員在設(shè)計(jì)的演化過程中,，以二十個(gè)氨基酸的組合排列,，架構(gòu)出難以數(shù)計(jì)的蛋白質(zhì)序列，然而這些序列不見的能夠存在于自然界中,，最有可能的因素,，就是因?yàn)榻Y(jié)構(gòu)的不穩(wěn)定 或是功能的不重要性，往往逃不過模擬演化的過程 研究人員從經(jīng)驗(yàn)中,，慢慢縮小目標(biāo) 最后選擇以黏附ATP的蛋白分子 大小約在 80個(gè)氨基酸左右,，的蛋白顆粒為目標(biāo)，并且進(jìn)一步的利用 3D結(jié)晶學(xué)的技術(shù),，分析最穩(wěn)定的結(jié)構(gòu)可能,，結(jié)果研究人員確實(shí)發(fā)現(xiàn)有兩個(gè)特殊的氨基酸，具有加強(qiáng)黏著力 易溶于水以及高耐熱性的特質(zhì),，很容易在演化的篩選中存活下來,。
科學(xué)家表示下一個(gè)目標(biāo)，就是利用這樣的一個(gè)模擬經(jīng)驗(yàn),，幫助設(shè)計(jì)具有治療作用的功能性蛋白質(zhì),。
原始出處:
PLoS ONE
Received: March 28, 2007; Accepted: April 25, 2007; Published: May 23, 2007
Structural Insights into the Evolution of a Non-Biological Protein: Importance of Surface Residues in Protein Fold Optimization
Matthew D. Smith1,2, Matthew A. Rosenow1,2, Meitian Wang2, James P. Allen2, Jack W. Szostak3, John C. Chaput1,2*
1 Center for BioOptical Nanotechnology, The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America, 2 Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona, United States of America, 3 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
Phylogenetic profiling of amino acid substitution patterns in proteins has led many to conclude that most structural information is carried by interior core residues that are solvent inaccessible. This conclusion is based on the observation that buried residues generally tolerate only conserved sequence changes, while surface residues allow more diverse chemical substitutions. This notion is now changing as it has become apparent that both core and surface residues play important roles in protein folding and stability. Unfortunately, the ability to identify specific mutations that will lead to enhanced stability remains a challenging problem. Here we discuss two mutations that emerged from an in vitro selection experiment designed to improve the folding stability of a non-biological ATP binding protein. These mutations alter two solvent accessible residues, and dramatically enhance the expression, solubility, thermal stability, and ligand binding affinity of the protein. The significance of both mutations was investigated individually and together, and the X-ray crystal structures of the parent sequence and double mutant protein were solved to a resolution limit of 2.8 and 1.65 Å, respectively. Comparative structural analysis of the evolved protein to proteins found in nature reveals that our non-biological protein evolved certain structural features shared by many thermophilic proteins. This experimental result suggests that protein fold optimization by in vitro selection offers a viable approach to generating stable variants of many naturally occurring proteins whose structures and functions are otherwise difficult to study.
