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1.
  总被引:2,自引:0,他引:2  
By means of Monte Carlo simulation, we investigated the equilibrium between folded and unfolded states of lattice model proteins. The amino acid sequences were designed to have pronounced energy minimum target conformations of different length and shape. For short fully compact (36-mer) proteins, the all-or-none transition from the unfolded state to the native state was observed. This was not always the case for longer proteins. Among 12 designed sequences with the native structure of a fully compact 48-mer, a simple all-or-none transition was observed in only three cases. For the other nine sequences, three states of behavior-the native, denatured, and intermediate states-were found. The contiguous part of the native structure (domain) was conserved in the intermediate state, whereas the remaining part was completely unfolded and structureless. These parts melted separately from each other.  相似文献   

2.
    
Franc Avbelj  John Moult 《Proteins》1995,23(2):129-141
Experimental evidence and theoretical models both suggest that protein folding begins by specific short regions of the polypeptide chain intermittently assuming conformations close to their final ones. The independent folding properties and small size of these folding initiation sites make them suitable subjects for computational methods aimed at deriving structure from sequence. We have used a torsion space Monte Carlo procedure together with an all-atom free energy function to investigate the folding of a set of such sites. The free energy function is derived by a potential of mean force analysis of experimental protein structures. The most important contributions to the total free energy are the local main chain electrostatics, main chain hydrogen bonds, and the burial of nonpolar area. Six proposed independent folding units and four control peptides 11–14 residues long have been investigated. Thirty Monte Carlo simulations were performed on each peptide, starting from different random conformations. Five of the six folding units adopted conformations close to the experimental ones in some of the runs. None of the controls did so, as expected. The generated conformations which are close to the experimental ones have among the lowest free energies encountered, although some less native like low free energy conformations were also found. The effectiveness of the method on these peptides, which have a wide variety of experimental conformations, is encouraging in two ways: First, it provides independent evidence that these regions of the sequences are able to adopt native like conformations early in folding, and therefore are most probably key components of the folding pathways. Second, it demonstrates that available simulation methods and free energy functions are able to produce reasonably accurate structures. Extensions of the methods to the folding of larger portions of proteins are suggested. © 1995 Wiley-Liss, Inc.  相似文献   

3.
An important idea that emerges from the energy landscape theory of protein folding is that subtle global features of the protein landscape can profoundly affect the apparent mechanism of folding. The relationship between various characteristic temperatures in the phase diagrams and landmarks in the folding funnel at fixed temperatures can be used to classify different folding behaviors. The one-dimensional picture of a folding funnel classifies folding kinetics into four basic scenarios, depending on the relative location of the thermodynamic barrier and the glass transition as a function of a single-order parameter. However, the folding mechanism may not always be quantitatively described by a single-order parameter. Several other order parameters, such as degree of secondary structure formation, collapse and topological order, are needed to establish the connection between minimalist models and proteins in the laboratory. In this article we describe a simple multidimensional funnel based on two-order parameters that measure the degree of collapse and topological order. The appearance of several different “mechanisms” is illustrated by analyzing lattice models with different potentials and sequences with different degrees of design. In most cases, the two-dimensional analysis leads to a classification of mechanisms totally in keeping with the one-dimensional scheme, but a topologically distinct scenario of fast folding with traps also emerges. The nature of traps depends on the relative location of the glass transition surface and the thermodynamic barrier in the multidimensional funnel. Proteins 32:136–158, 1998. © 1998 Wiley-Liss, Inc.  相似文献   

4.
    
Wang P  Klimov DK 《Proteins》2008,70(3):925-937
We use lattice protein models and Monte Carlo simulations to study cotranslational folding of small single domain proteins. We show that the assembly of native structure begins during late extrusion stages, but final formation of native state occurs during de novo folding, when all residues are extruded. There are three main results in our study. First, for the sequences displaying two-state refolding mechanism de novo cotranslational folding pathway differs from that sampled in in vitro refolding. The change in folding pathways is due to partial assembly of native interactions during extrusion that results in different starting conditions for in vitro refolding and for de novo cotranslational folding. For small single domain proteins cotranslational folding is slower than in vitro refolding, but is generally fast enough to be completed before the release from a ribosome. Second, we found that until final stages of biosynthesis cotranslational folding is essentially equilibrium. This observation is explained by low stability of structured states for partially extruded chains. Finally, our data suggest that the proteins, which refold in vitro slowly via intermediates, complete their de novo folding after the release from a ribosome. Comparison of our lattice cotranslational simulations with recent experimental and computational studies is discussed.  相似文献   

5.
Generic features associated with the adsorption of proteins on solid surfaces are reviewed within the framework of the hydrophobic-polar (HP) lattice protein model. The thermodynamic behaviour and structural properties of various HP protein sequences interacting with attractive surfaces have been studied using extensive Wang–Landau sampling with different types of surfaces, each of which attracts either: all monomers, only hydrophobic (H) monomers or only polar (P) monomers, respectively. Consequently, different types of folding behaviour occur for varied surface strengths. Analysis of the combined patterns of various structural observables, e.g. the derivatives of the number of interaction contacts, together with the specific heat, leads to the identification of fundamental categories of folding and transition hierarchies. We also inferred a connection between the transition categories and the relative surface strengths, i.e. the ratios of the surface attractive strengths to the intra-chain attraction among H monomers. Thus, we believe that the folding hierarchies and identification scheme are generic for different HP sequences interacting with attractive surfaces, regardless of the chain length, sequence or surface attraction.  相似文献   

6.
    
Verkhivker GM 《Biopolymers》2004,75(5):420-433
Conformational transitions coupled to binding are studied for the p27(Kip1) protein which undergoes a functional disorder-to-order folding transition during tertiary complex formation with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) binary complex. Temperature-induced Monte Carlo simulations of p27(Kip1) unfolding-unbinding carried out from the crystal structure of the tertiary complex have revealed a systematic trend in the hierarchy of structural loss for p27(Kip1) and a considerable difference in mobility of p27(Kip1) secondary structure elements. The most persistent interactions of p27(Kip1) at the intermolecular interface during unfolding-unbinding simulations are formed by beta-hairpin and beta-strand that on average maintain their structural integrity considerably longer than other p27(Kip1) elements. We have found that the ensemble of unfolded p27(Kip1) conformations is characterized by transitions between mostly unbound, collapsed conformations and entropically favorable p27(Kip1) conformations, which are weakly bound to the cyclin A side of the binary complex. The results of this study are consistent with the experimental evidence pointing to this region of the intermolecular interface as a potential initiation docking site during binding reaction and may reconcile conflicting experimental hypotheses on the recognition of substrate recruitment motifs.  相似文献   

7.
We present a method with the potential to generate a library of coil segments from first principles. Proteins are built from α‐helices and/or β‐strands interconnected by these coil segments. Here, we investigate the conformational determinants of short coil segments, with particular emphasis on chain turns. Toward this goal, we extracted a comprehensive set of two‐, three‐, and four‐residue turns from X‐ray–elucidated proteins and classified them by conformation. A remarkably small number of unique conformers account for most of this experimentally determined set, whereas remaining members span a large number of rare conformers, many occurring only once in the entire protein database. Factors determining conformation were identified via Metropolis Monte Carlo simulations devised to test the effectiveness of various energy terms. Simulated structures were validated by comparison to experimental counterparts. After filtering rare conformers, we found that 98% of the remaining experimentally determined turn population could be reproduced by applying a hydrogen bond energy term to an exhaustively generated ensemble of clash‐free conformers in which no backbone polar group lacks a hydrogen‐bond partner. Further, at least 90% of longer coil segments, ranging from 5‐ to 20 residues, were found to be structural composites of these shorter primitives. These results are pertinent to protein structure prediction, where approaches can be divided into either empirical or ab initio methods. Empirical methods use database‐derived information; ab initio methods rely on physical–chemical principles exclusively. Replacing the database‐derived coil library with one generated from first principles would transform any empirically based method into its corresponding ab initio homologue.  相似文献   

8.
    
The 3-dimensional optimization of the electrostatic interactions between the charged amino acid residues was studied by Monte Carlo simulations on an extended representative set of 141 protein structures with known atomic coordinates. The proteins were classified by different functional and structural criteria, and the optimization of the electrostatic interactions was analyzed. The optimization parameters were obtained by comparison of the contribution of charge-charge interactions to the free energy of the native protein structures and for a large number of randomly distributed charge constellations obtained by the Monte Carlo technique. On the basis of the results obtained, one can conclude that the charge-charge interactions are better optimized in the enzymes than in the proteins without enzymatic functions. Proteins that belong to the mixed αβ folding type are electrostatically better optimized than pure α-helical or β-strand structures. Proteins that are stabilized by disulfide bonds show a lower degree of electrostatic optimization. The electrostatic interactions in a native protein are effectively optimized by rejection of the conformers that lead to repulsive charge-charge interactions. Particularly, the rejection of the repulsive contacts seems to be a major goal in the protein folding process. The dependence of the optimization parameters on the choice of the potential function was tested. The majority of the potential functions gave practically identical results.  相似文献   

9.
    
For computational studies of protein folding, proteins with both helical and β‐sheet secondary structure elements are very challenging, as they expose subtle biases of the physical models. Here, we present reproducible folding of a 92 residue α/β protein (residues 3–94 of Top7, PDB ID: 1QYS) in computer simulations starting from random initial conformations using a transferable physical model which has been previously shown to describe the folding and thermodynamic properties of about 20 other smaller proteins of different folds. Top7 is a de novo designed protein with two α‐helices and a five stranded β‐sheet. Experimentally, it is known to be unusually stable for its size, and its folding transition distinctly deviates from the two‐state behavior commonly seen in natural single domain proteins. In our all‐atom implicit solvent parallel tempering Monte Carlo simulations, Top7 shows a rapid transition to a group of states with high native‐like secondary structure, and a much slower subsequent transition to the native state with a root mean square deviation of about 3.5 Å from the experimentally determined structure. Consistent with experiments, we find Top7 to be thermally extremely stable, although the simulations also find a large number of very stable non‐native states with high native‐like secondary structure. Proteins 2013; 81:1446–1456. © 2013 Wiley Periodicals, Inc.  相似文献   

10.
    
The main problems found in designing drugs are those of optimizing the drug-target interaction and of avoiding the insurgence of resistance. We suggest a scheme for the design of inhibitors that can be used as leads for the development of a drug and that do not face either of these problems, and then apply it to the case of HIV-1-PR. It is based on the knowledge that the folding of single-domain proteins, such as each of the monomers forming the HIV-1-PR homodimer, is controlled by local elementary structures (LES), stabilized by local contacts among hydrophobic, strongly interacting, and highly conserved amino acids that play a central role in the folding process. Because LES have evolved over many generations to recognize and strongly interact with each other so as to make the protein fold fast and avoid aggregation with other proteins, highly specific (and thus little toxic) as well as effective folding-inhibitor molecules suggest themselves: short peptides (or eventually their mimetic molecules) displaying the same amino acid sequence of that of LES (p-LES). Aside from being specific and efficient, these inhibitors are expected not to induce resistance; in fact, mutations in HIV-1-PR that successfully avoid the action of p-LES imply the destabilization of one or more LES and thus should lead to protein denaturation. Making use of Monte Carlo simulations, we first identify the LES of the HIV-1-PR and then show that the corresponding p-LES peptides act as effective inhibitors of the folding of the protease.  相似文献   

11.
Continuum solvation models that estimate free energies of solvation as a function of solvent accessible surface area are computationally simple enough to be useful for predicting protein conformation. The behavior of three such solvation models has been examined by applying them to the minimization of the conformational energy of bovine pancreatic trypsin inhibitor. The models differ only with regard to how the constants of proportionality between free energy and surface area were derived. Each model was derived by fitting to experimentally measured equilibrium solution properties. For two models, the solution property was free energy of hydration. For the third, the property was NMR coupling constants. The purpose of this study is to determine the effect of applying these solvation models to the nonequilibrium conformations of a protein arising in the course of global searches for conformational energy minima. Two approaches were used: (1) local energy minimization of an ensemble of conformations similar to the equilibrium conformation and (2) global search trajectories using Monte Carlo plus minimization starting from a single conformation similar to the equilibrium conformation. For the two models derived from free energy measurements, it was found that both the global searches and local minimizations yielded conformations more similar to the X-ray crystallographic structures than did searches or local minimizations carried out in the absence of a solvation component of the conformational energy. The model derived from NMR coupling constants behaved similarly to the other models in the context of a global search trajectory. For one of the models derived from measured free energies of hydration, it was found that minimization of an ensemble of near-equilibrium conformations yielded a new ensemble in which the conformation most similar to the X-ray determined structure PTI4 had the lowest total free energy. Despite the simplicity of the continuum solvation models, the final conformation generated in the trajectories for each of the models exhibited some of the characteristics that have been reported for conformations obtained from molecular dynamics simulations in the presence of a bath of explicit water molecules. They have smaller root mean square (rms) deviations from the experimentally determined conformation, fewer incorrect hydrogen bonds, and slightly larger radii of gyration than do conformations derived from search trajectories carried out in the absence of solvent.  相似文献   

12.
    
Favrin G  Irbäck A  Wallin S 《Proteins》2002,47(2):99-105
A reduced protein model with five to six atoms per amino acid and five amino acid types is developed and tested on a three-helix-bundle protein, a 46-amino acid fragment from staphylococcal protein A. The model does not rely on the widely used Go approximation, which ignores non-native interactions. We find that the collapse transition is considerably more abrupt for the protein A sequence than for random sequences with the same composition. The chain collapse is found to be at least as fast as helix formation. Energy minimization restricted to the thermodynamically favored topology gives a structure that has a root-mean-square deviation of 1.8 A from the native structure. The sequence-dependent part of our potential is pairwise additive. Our calculations suggest that fine-tuning this potential by parameter optimization is of limited use.  相似文献   

13.
There is considerable experimental evidence that the cooperativity of protein folding resides in the transition from the molten globule to the native state. The objective of this study is to examine whether simplified models can reproduce this cooperativity and if so, to identify its origin. In particular, the thermodynamics of the conformational transition of a previously designed sequence (A. Kolinski, W. Galazka, and J. Skolnick, J. Chem. Phys. 103: 10286–10297, 1995), which adopts a very stable Greek-key β-barrel fold has been investigated using the entropy Monte Carlo sampling (ESMC) technique of Hao and Scheraga (M.-H. Hao and H.A. Scheraga, J. Phys. Chem. 98: 9882–9883, 1994). Here, in addition to the original potential, which includes one body and pair interactions between side chains, the force field has been supplemented by two types of multi-body potentials describing side chain interactions. These potentials facilitate the proteinlike pattern of side chain packing and consequently increase the cooperativity of the folding process. Those models that include an explicit cooperative side chain packing term exhibit a well-defined all-or-none transition from a denatured, random coil state to a high-density, well-defined, nativelike low-energy state. By contrast, models lacking such a term exhibit a conformational transition that is essentially continuous. Finally, an examination of the conformations at the free-energy barrier between the native and denatured states reveals that they contain a substantial amount of native-state secondary structure, about 50% of the native contacts, and have an average root mean square radius of gyration that is about 15% larger than native. © 1996 Wiley-Liss, Inc.  相似文献   

14.
    
Rossinsky E  Srebnik S 《Biopolymers》2005,79(5):259-268
Ensemble growth Monte Carlo (EGMC) and dynamic Monte Carlo (DMC) simulations are used to study sequential folding and thermodynamic stability of hydrophobic-polar (HP) chains that fold to a compact structure. Molecularly imprinted cavities are modeled as hard walls having sites that are attractive to specific polar residues on the chain. Using EGMC simulation, we find that the folded conformation can be stabilized using a small number of carefully selected residue-specific sites while a random selection of surface-bound residues may only slightly contribute toward stabilizing the folded conformation, and in some cases may hinder the folding of the chain. DMC simulations of the surface-bound chain confirm increased stability of the folded conformation over a free chain. However, a different trend of the equilibrium population of folded chains as a function of residue-external site interactions is predicted with the two simulation methods.  相似文献   

15.
    
It is well established that protein structures are more conserved than protein sequences. One-third of all known protein structures can be classified into ten protein folds, which themselves are composed mainly of alpha-helical hairpin, beta hairpin, and betaalphabeta supersecondary structural elements. In this study, we explore the ability of a recent Monte Carlo-based procedure to generate the 3D structures of eight polypeptides that correspond to units of supersecondary structure and three-stranded antiparallel beta sheet. Starting from extended or misfolded compact conformations, all Monte Carlo simulations show significant success in predicting the native topology using a simplified chain representation and an energy model optimized on other structures. Preliminary results on model peptides from nucleotide binding proteins suggest that this simple protein folding model can help clarify the relation between sequence and topology.  相似文献   

16.
    
Favrin G  Irbäck A  Wallin S 《Proteins》2004,54(1):8-12
Z(SPA-1) is an engineered protein that binds to its parent, the three-helix-bundle Z domain of staphylococcal protein A. Uncomplexed Z(SPA-1) shows a reduced helix content and a melting behavior that is less cooperative, compared with the wild-type Z domain. Here we show that the difference in folding behavior between these two sequences can be partly understood in terms of an off-lattice model with 5-6 atoms per amino acid and a minimalistic potential, in which folding is driven by backbone hydrogen bonding and effective hydrophobic attraction.  相似文献   

17.
    
The folding mechanism of the Villin headpiece (HP36) is studied by means of a novel approach which entails an initial coarse-grained Monte Carlo (MC) scheme followed by all-atom molecular dynamics (MD) simulations in explicit solvent. The MC evolution occurs in a simplified free-energy landscape and allows an efficient selection of marginally-compact structures which are taken as viable initial conformations for the MD. The coarse-grained MC structural representation is connected to the one with atomic resolution through a \"fine-graining\" reconstruction algorithm. This two-stage strategy is used to select and follow the dynamics of seven different unrelated conformations of HP36. In a notable case the MD trajectory rapidly evolves towards the folded state, yielding a typical root-mean-square deviation (RMSD) of the core region of only 2.4 A from the closest NMR model (the typical RMSD over the whole structure being 4.0 A). The analysis of the various MC-MD trajectories provides valuable insight into the details of the folding and mis-folding mechanisms and particularly about the delicate influence of local and nonlocal interactions in steering the folding process.  相似文献   

18.
    
Imamura H  Chen JZ 《Proteins》2006,63(3):555-570
We study the dependence of folding time, nucleation site, and stability of a model beta-hairpin on the location of a cross-strand hydrophobic pair, using a coarse-grained off-lattice model with the aid of Monte Carlo simulations. Our simulations have produced 6500 independent folding trajectories dynamically, forming the basis for extensive statistical analysis. Four folding pathways, zipping-out, middle-out, zipping-in, and reptation, have been closely monitored and discussed in all seven sequences studied. A hydrophobic pair placed near the beta-turn or in the middle section effectively speed up folding; a hydrophobic pair placed close to the terminal ends or next to the beta-turn encourages stability of the entire chain.  相似文献   

19.
  总被引:1,自引:0,他引:1  
We used dynamic Monte Carlo simulation to investigate how changing the rate of chemical or thermal renaturation affects the folding and aggregation behavior of a system of simple, two-dimensional lattice protein molecules. Four renaturation methods were simulated: infinitely slow cooling; slow but finite cooling; quenching; and pulse renaturation. The infinitely slow cooling method, which is equivalent to dialysis or diafiltration, provides refolding yields that are relatively high and aggregates that are relatively small (mostly dimers or trimers). The slow but finite cooling method, which is equivalent to multiple-step dilution, provides refolding yields that are almost as high as those observed in the infinitely slow cooling case, but in a relatively short period of time. Quenching, which is equivalent to one-step dilution or quick quenching, is extremely slow and has low re- folding yields. A maximum appears in the refolding yield as a function of denaturant concentration in the simulation but disappears after a very long duration. Finally, the pulse renaturation method provides refolding yields that are substantially higher than those observed in the other three methods, even at high packing fractions. As in the early stages of quenching, there is a maximum in the refolding yield as a function of denaturant concentration when relatively large numbers of denatured chains are added to the refolding solution at each step.  相似文献   

20.
从氨基酸序列预测蛋白质折叠速率   总被引:1,自引:0,他引:1       下载免费PDF全文
蛋白质折叠速率预测是当今生物物理学最具挑战性的课题之一.近年来,许多科研工作者开展了大量的研究工作来探索折叠速率的决定因素,许多参数和方法被相继提出.但氨基酸残基间的相互作用、氨基酸的序列顺序等信息对折叠速率的影响从未被提及.采用伪氨基酸组成的方法提取氨基酸的序列顺序信息,利用蒙特卡洛方法选择最佳特征因子,建立线性回归模型进行折叠速率预测.该方法能在不需要任何(显示)结构信息的情况下,直接从蛋白质的氨基酸序列出发对折叠速率进行预测.在Jackknife交互检验方法的验证下,对含有99个蛋白质的数据集,发现折叠速率的预测值与实验值有很好的相关性,相关系数能达到0.81,预测误差仅为2.54.这一精度明显优于其他基于序列的方法,充分说明蛋白质的序列顺序信息是影响蛋白质折叠速率的重要因素.  相似文献   

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