Towards a consistent modeling of protein thermodynamic and kinetic cooperativity: How applicable is the transition state picture to folding and unfolding?

被引:85
作者
Kaya, H
Chan, HS [1 ]
机构
[1] Univ Toronto, Dept Biochem, Fac Med, Toronto, ON M58 1A8, Canada
[2] Univ Toronto, Dept Med Genet & Microbiol, Fac Med, Toronto, ON M58 1A8, Canada
基金
英国医学研究理事会;
关键词
calorimetric cooperativity; single-exponential kinetics; rugged landscape; unfolding; chevron plot;
D O I
10.1006/jmbi.2001.5266
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
To what extent do general features of folding/unfolding kinetics of small globular proteins follow from their thermodynamic properties? To address this question, we investigate a new simplifed protein chain model that embodies a cooperative interplay between local conformational preferences and hydrophobic burial. The present four-helix-bundle 55mer model exhibits protein-like calorimetric two-state cooperativity. It rationalizes native-state hydrogen exchange observations. Our analysis indicates that a coherent, self-consistent physical account of both the thermodynamic and kinetic properties of the model leads naturally to the concept of a native state ensemble that encompasses considerable conformational fluctuations. Such a multiple-conformation native state is seen to involve conformational states similar to those revealed by native-state hydrogen exchange. Many of these conformational states are predicted to lie below native baselines commonly used in interpreting calorimetric data. Folding and unfolding kinetics are studied under a range of intrachain interaction strengths as in experimental chevron plots. Kinetically determined transition midpoints match well with their thermodynamic counterparts. Kinetic relaxations are found to be essentially single-exponential over an extended range of model interaction strengths. This includes the entire unfolding regime and a significant part of a folding regime with a chevron rollover, as has been observed for real proteins that fold with non-two-state kinetics. The transition state picture of protein folding and unfolding is evaluated by comparing thermodynamic free energy profiles with actual kinetic rates. These analyses suggest that some chevron rollovers may arise from an internal frictional effect that increasingly impedes chain motions with more native conditions, rather than being caused by discrete deadtime folding intermediates or shifts of the transition state peak as previously posited. (C) 2002 Academic Press.
引用
收藏
页码:899 / 909
页数:11
相关论文
共 84 条
[1]   FREE-ENERGY LANDSCAPE FOR PROTEIN-FOLDING KINETICS - INTERMEDIATES, TRAPS, AND MULTIPLE PATHWAYS IN THEORY AND LATTICE MODEL SIMULATIONS [J].
ABKEVICH, VI ;
GUTIN, AM ;
SHAKHNOVICH, EI .
JOURNAL OF CHEMICAL PHYSICS, 1994, 101 (07) :6052-6062
[2]   Prediction of protein-folding mechanisms from free-energy landscapes derived from native structures [J].
Alm, E ;
Baker, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11305-11310
[3]   SOLVENT DENATURATION AND STABILIZATION OF GLOBULAR-PROTEINS [J].
ALONSO, DOV ;
DILL, KA .
BIOCHEMISTRY, 1991, 30 (24) :5974-5985
[4]  
[Anonymous], CURRENT TOPICS COMPU
[5]  
Arai M, 2000, ADV PROTEIN CHEM, V53, P209
[6]   PROTEIN-FOLDING INTERMEDIATES - NATIVE-STATE HYDROGEN-EXCHANGE [J].
BAI, YW ;
SOSNICK, TR ;
MAYNE, L ;
ENGLANDER, SW .
SCIENCE, 1995, 269 (5221) :192-197
[7]   A surprising simplicity to protein folding [J].
Baker, D .
NATURE, 2000, 405 (6782) :39-42
[8]  
Bilsel O, 2000, ADV PROTEIN CHEM, V53, P153
[9]   SIDE-CHAIN ENTROPY AND PACKING IN PROTEINS [J].
BROMBERG, S ;
DILL, KA .
PROTEIN SCIENCE, 1994, 3 (07) :997-1009
[10]   FUNNELS, PATHWAYS, AND THE ENERGY LANDSCAPE OF PROTEIN-FOLDING - A SYNTHESIS [J].
BRYNGELSON, JD ;
ONUCHIC, JN ;
SOCCI, ND ;
WOLYNES, PG .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 1995, 21 (03) :167-195