Effects of confinement in chaperonin assisted protein folding: Rate enhancement by decreasing the roughness of the folding energy landscape

被引:99
作者
Baumketner, A
Jewett, A
Shea, JE [1 ]
机构
[1] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA
[2] Inst Condensed Matter Phys, UA-79011 Lvov, Ukraine
基金
美国国家科学基金会;
关键词
chaperonin; protein folding; energy landscape; minimalist off-lattice model; computer simulation;
D O I
10.1016/S0022-2836(03)00929-X
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
Chaperonins, such as the GroE complex of the bacteria Escherichia coli, assist the folding of proteins under non-permissive folding conditions by providing a cavity in which the newly translated or translocated protein can be encapsulated. Whether the chaperonin cage plays a passive role in protecting the protein from aggregation, or an active role in accelerating folding rates, remains a matter of debate. Here, we investigate the role of confinement in chaperonin mediated folding through molecular dynamics simulations. We designed a substrate protein with an alpha/beta sandwich fold, a common structural motif found in GroE substrate proteins and confined it to a spherical hydrophilic cage which mimicked the interior of the GroEL/ES cavity. The thermodynamics and kinetics of folding were studied over a wide range of temperature and cage radii. Confinement was seen to significantly raise the collapse temperature, T-c, as a result of the associated entropy loss of the unfolded state. The folding temperature, T-f, on the other hand, remained unaffected by encapsulation, a consequence of the folding mechanism of this protein that involves an initial collapse to a compact misfolded state prior to rearranging to the native state. Folding rates were observed to be either accelerated or retarded compared to bulk folding rates, depending on the temperature of the simulation. Rate enhancements due to confinement were observed only at temperatures above the temperature T-m, which corresponds to the temperature at which the protein folds fastest. For this protein, T-m lies above the folding temperature, T-f, implying that encapsulation alone will not lead to a rate enhancement under conditions where the native state is stable (T < T-f). For confinement to positively impact folding rates under physiological conditions, it is hence necessary for the protein to exhibit a folding transition above the temperature at which it exhibits its fastest folding rate (T-m < T-f). We designed a protein with this property by reducing the energetic frustration in the original alpha/beta sandwich substrate protein. The modified protein exhibited a twofold acceleration in folding rates upon encapsulation. This rate enhancement is due to a mechanistic change in folding involving the elimination, upon encapsulation, of accessible local energy minima corresponding to structures with large radii of gyration. For this protein, confinement hence plays more than the role of a passive cage, but rather adopts an active role, accelerating folding rates by decreasing the roughness of the energy landscape of the protein. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:701 / 713
页数:13
相关论文
共 52 条
[1]  
ALLEN MP, 1986, COMPUTER SIMULATION
[2]  
[Anonymous], FOLDING DESIGN
[3]   Diffusive dynamics of protein folding studied by molecular dynamics simulations of an off-lattice model [J].
Baumketner, A ;
Hiwatari, Y .
PHYSICAL REVIEW E, 2002, 66 (01)
[4]   Exploring the kinetic requirements for enhancement of protein folding rates in the GroEL cavity [J].
Betancourt, MR ;
Thirumalai, D .
JOURNAL OF MOLECULAR BIOLOGY, 1999, 287 (03) :627-644
[5]   Dual function of protein confinement in chaperonin-assisted protein folding [J].
Brinker, A ;
Pfeifer, G ;
Kerner, MJ ;
Naylor, DJ ;
Hartl, FU ;
Hayer-Hartl, M .
CELL, 2001, 107 (02) :223-233
[6]   INTERMEDIATES AND BARRIER CROSSING IN A RANDOM ENERGY-MODEL (WITH APPLICATIONS TO PROTEIN FOLDING) [J].
BRYNGELSON, JD ;
WOLYNES, PG .
JOURNAL OF PHYSICAL CHEMISTRY, 1989, 93 (19) :6902-6915
[7]   KINETICS AND THERMODYNAMICS OF FOLDING IN MODEL PROTEINS [J].
CAMACHO, CJ ;
THIRUMALAI, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (13) :6369-6372
[8]   ENERGY LANDSCAPES AND THE COLLAPSE DYNAMICS OF HOMOPOLYMERS [J].
CHAN, HS ;
DILL, KA .
JOURNAL OF CHEMICAL PHYSICS, 1993, 99 (03) :2116-2127
[9]  
Chan HS, 1996, PROTEINS, V24, P345
[10]  
CHAN HS, 1997, MONTE CARLO APPROACH