Surveying a local fitness landscape of a protein with epistatic sites for the study of directed evolution

被引:26
作者
Aita, T
Hamamatsu, N
Nomiya, Y
Uchiyama, H
Shibanaka, Y
Husimi, Y [1 ]
机构
[1] Saitama Univ, Dept Funct Mat Sci, Saitama 3388570, Japan
[2] Novartis Pharma KK, Tsukuba Res Inst, Tsukuba, Ibaraki 3002611, Japan
关键词
epistasis; mutation scrambling; mutational additivity; sequence space; thermostability;
D O I
10.1002/bip.10126
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We present a method for analysis of a fitness landscape of a biopolymer with significantly epistatic sites. The analysis is based on a quasi-additive fitness model. The fitness model is constructed with additive terms conducted by, "site-fitness" and epistatic terms conducted by "pair-fitness," where the site-fitness is a fitness contribution from an independent residue and the pair-fitness is a fitness contribution from a pair of epistatic residues. As a case study, we analyzed the sequence-fitness data for 45 clones of thermostable prolyl endopeptidase mutants. They were generated by a mutation scrambling method, which can accumulate advantageous mutations. The fitness contributions from 14 single-point mutations including E67Q and Q656R were identified by the analysis. As a result, we found that the fitness model with a significant epistatic term by a pair of the 67th site and 656th site was in good agreement with the experimental data and that the explored landscape in the binary 14-dimensional sequence space is still a mountainous landscape with twin peaks. The validity was supported by, the analysis of mutant fitness distributions derived from another mutation scrambling experiment and by (3D) structural data. (C) 2002 Wiley Periodicals, Inc.
引用
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页码:95 / 105
页数:11
相关论文
共 14 条
[1]   Theory of evolutionary molecular engineering through simultaneous accumulation of advantageous mutations [J].
Aita, T ;
Husimi, Y .
JOURNAL OF THEORETICAL BIOLOGY, 2000, 207 (04) :543-556
[2]   Fitness spectrum among random mutants on Mt Fuji-type fitness landscape [J].
Aita, T ;
Husimi, Y .
JOURNAL OF THEORETICAL BIOLOGY, 1996, 182 (04) :469-485
[3]  
Aita T, 2000, BIOPOLYMERS, V54, P64, DOI 10.1002/(SICI)1097-0282(200007)54:1<64::AID-BIP70>3.0.CO
[4]  
2-R
[5]   A cross-section of the fitness landscape of dihydrofolate reductase [J].
Aita, T ;
Iwakura, M ;
Husimi, Y .
PROTEIN ENGINEERING, 2001, 14 (09) :633-638
[6]  
[Anonymous], ORIGIN ORDER
[7]  
CHARLIER CVL, 1931, APPL THEORIE PROBABI
[8]   MACROMOLECULAR EVOLUTION - DYNAMICAL ORDERING IN SEQUENCE SPACE [J].
EIGEN, M .
BERICHTE DER BUNSEN-GESELLSCHAFT-PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 1985, 89 (06) :658-667
[9]  
Miller J. C., 1988, STAT ANAL CHEM
[10]   PROTEIN EVOLUTION ON PARTIALLY CORRELATED LANDSCAPES [J].
PERELSON, AS ;
MACKEN, CA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (21) :9657-9661