Synergy between simulation and experiment in describing the energy landscape of protein folding

被引:103
作者
Ladurner, AG
Itzhaki, LS
Daggett, V
Fersht, AR
机构
[1] Univ Cambridge, Ctr Mrc, Chem Lab, Cambridge CB2 2QH, England
[2] Univ Cambridge, Ctr Mrc, Cambridge Ctr Prot Engn, Cambridge CB2 2QH, England
[3] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA
关键词
D O I
10.1073/pnas.95.15.8473
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
Experimental data from protein engineering studies and NMR spectroscopy have been used by theoreticians to develop algorithms for helix propensity and to benchmark computer simulations of folding pathways and energy landscapes. Molecular dynamic simulations of the unfolding of chymotrypsin inhibitor 2 (CI2) have provided detailed structural models of the transition state ensemble for unfolding/folding of the protein. We now have used the simulated transition state structures to design faster folding mutants of CI2, The models pinpoint a number of unfavorable local interactions at the carboxyl terminus of the single alpha-helis and in the protease-binding loop region of CI2, By removing these interactions or replacing them with stabilizing ones, we have increased the rate of folding of the protein up to 40-fold (tau = 0.4 ms). This correspondence, and other examples of agreement between experiment and theory in general, Phi-values and molecular dynamics simulations, in particular, suggest that significant progress has been made toward describing complete folding pathways at atomic resolution by combining experiment and simulation.
引用
收藏
页码:8473 / 8478
页数:6
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