Computational prediction of native protein ligand-binding and enzyme active site sequences

被引:34
|
作者
Chakrabarti, R [1 ]
Klibanov, AM
Friesner, RA
机构
[1] Columbia Univ, Dept Chem, New York, NY 10027 USA
[2] Columbia Univ, Ctr Biomol Simulat, New York, NY 10027 USA
[3] MIT, Dept Chem, Cambridge, MA 02139 USA
[4] MIT, Div Biol Engn, Cambridge, MA 02139 USA
关键词
computational protein design; design enzyme; protein evolution;
D O I
10.1073/pnas.0504023102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recent studies reveal that the core sequences of many proteins were nearly optimized for stability by natural evolution. Surface residues, by contrast, are not so optimized, presumably because protein function is mediated through surface interactions with other molecules. Here, we sought to determine the extent to which the sequences of protein ligand-binding and enzyme active sites could be predicted by optimization of scoring functions based on protein ligand-binding affinity rather than structural stability. Optimization of binding affinity under constraints on the folding free energy correctly predicted 83% of amino acid residues (94% similar) in the binding sites of two model receptor-ligand complexes, streptavidin-biotin and glucose-binding protein. To explore the applicability of this methodology to enzymes, we applied an identical algorithm to the active sites of diverse enzymes from the peptidase, beta-gal, and nucleotide synthase families. Although simple optimization of binding affinity reproduced the sequences of some enzyme active sites with high precision, imposition of additional, geometric constraints on side-chain conformations based on the catalytic mechanism was required in other cases. With these modifications, our sequence optimization algorithm correctly predicted 78% of residues from all of the enzymes, with 83% similar to native (90% correct, with 95% similar, excluding residues with high variability in multiple sequence alignments). Furthermore, the conformations of the selected side chains were often correctly predicted within crystallographic error. These findings suggest that simple selection pressures may have played a predominant role in determining the sequences of ligand-binding and active sites in proteins.
引用
收藏
页码:10153 / 10158
页数:6
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