PREDICTION OF THE ACTIVITY AND STABILITY EFFECTS OF SITE-DIRECTED MUTAGENESIS ON A PROTEIN CORE

被引:37
作者
VANGUNSTEREN, WF
MARK, AE
机构
[1] Department of Physical Chemistry Swiss Federal Institute, Technology Zuerich ETH Zentrum
关键词
COMPUTER SIMULATION; PROTEIN STABILITY; PROTEIN ACTIVITY; PREDICTION;
D O I
10.1016/0022-2836(92)90895-Q
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
When theoretical methods are used to predict the properties of a given system, such as the effects of the substitution of a specific amino acid on the activity or stability of a protein as a whole, the accuracy of the prediction is directly dependent on the validity of the underlying model. A common error, however, is to attempt to improve a basically crude model by performing one aspect of the calculation in a rigorous manner. The accuracy of the model as a whole will remain limited by the crudest approximation or weakest assumption. To demonstrate the principle that nothing can be gained by performing extensive calculations using a basically crude underlying model we compare the predictive power of three models in relation to activity and stability data for 78 triple-site sequence variants of the λ-repressor protein. This system has recently been analysed in terms of a conceptionally simple, but computationally elaborate model for the prediction of the energy of a protein in which amino acid residues in the core of the protein have been mutated. We show that comparable, if not better agreement with the experimental data can be reached using either of two much simpler models, based on straightforward structural considerations, which do not require elaborate calculations on a computer. © 1992.
引用
收藏
页码:389 / 395
页数:7
相关论文
共 11 条
[1]  
BEVERIDGE DL, 1989, ANNU REV BIOPHYS BIO, V18, P431, DOI 10.1146/annurev.biophys.18.1.431
[2]   SOLVATION ENERGY IN PROTEIN FOLDING AND BINDING [J].
EISENBERG, D ;
MCLACHLAN, AD .
NATURE, 1986, 319 (6050) :199-203
[3]   STRUCTURE-ACTIVITY-RELATIONSHIPS IN ENGINEERED PROTEINS - ANALYSIS OF USE OF BINDING-ENERGY BY LINEAR FREE-ENERGY RELATIONSHIPS [J].
FERSHT, AR ;
LEATHERBARROW, RJ ;
WELLS, TNC .
BIOCHEMISTRY, 1987, 26 (19) :6030-6038
[4]  
JORDAN SR, 1988, SCIENCE, V242, P893, DOI 10.1126/science.3187530
[5]   FREE-ENERGIES OF HYDRATION OF SOLUTE MOLECULES .1. IMPROVEMENT OF THE HYDRATION SHELL-MODEL BY EXACT COMPUTATIONS OF OVERLAPPING VOLUMES [J].
KANG, YK ;
NEMETHY, G ;
SCHERAGA, HA .
JOURNAL OF PHYSICAL CHEMISTRY, 1987, 91 (15) :4105-4109
[6]   ENERGETICS OF COMPLEMENTARY SIDE-CHAIN PACKING IN A PROTEIN HYDROPHOBIC CORE [J].
KELLIS, JT ;
NYBERG, K ;
FERSHT, AR .
BIOCHEMISTRY, 1989, 28 (11) :4914-4922
[7]   ACCURATE PREDICTION OF THE STABILITY AND ACTIVITY EFFECTS OF SITE-DIRECTED MUTAGENESIS ON A PROTEIN CORE [J].
LEE, C ;
LEVITT, M .
NATURE, 1991, 352 (6334) :448-451
[8]   PREDICTION OF PROTEIN SIDE-CHAIN CONFORMATION BY PACKING OPTIMIZATION [J].
LEE, C ;
SUBBIAH, S .
JOURNAL OF MOLECULAR BIOLOGY, 1991, 217 (02) :373-388
[9]   THE ROLE OF INTERNAL PACKING INTERACTIONS IN DETERMINING THE STRUCTURE AND STABILITY OF A PROTEIN [J].
LIM, WA ;
SAUER, RT .
JOURNAL OF MOLECULAR BIOLOGY, 1991, 219 (02) :359-376
[10]   COMPARING THE POLARITIES OF THE AMINO-ACIDS - SIDE-CHAIN DISTRIBUTION COEFFICIENTS BETWEEN THE VAPOR-PHASE, CYCLOHEXANE, 1-OCTANOL, AND NEUTRAL AQUEOUS-SOLUTION [J].
RADZICKA, A ;
WOLFENDEN, R .
BIOCHEMISTRY, 1988, 27 (05) :1664-1670