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1.
Ab initio protein folding is one of the major unsolved problems in computational biology owing to the difficulties in force field design and conformational search. We developed a novel program, QUARK, for template-free protein structure prediction. Query sequences are first broken into fragments of 1-20 residues where multiple fragment structures are retrieved at each position from unrelated experimental structures. Full-length structure models are then assembled from fragments using replica-exchange Monte Carlo simulations, which are guided by a composite knowledge-based force field. A number of novel energy terms and Monte Carlo movements are introduced and the particular contributions to enhancing the efficiency of both force field and search engine are analyzed in detail. QUARK prediction procedure is depicted and tested on the structure modeling of 145 nonhomologous proteins. Although no global templates are used and all fragments from experimental structures with template modeling score >0.5 are excluded, QUARK can successfully construct 3D models of correct folds in one-third cases of short proteins up to 100 residues. In the ninth community-wide Critical Assessment of protein Structure Prediction experiment, QUARK server outperformed the second and third best servers by 18 and 47% based on the cumulative Z-score of global distance test-total scores in the FM category. Although ab initio protein folding remains a significant challenge, these data demonstrate new progress toward the solution of the most important problem in the field. 相似文献
2.
In this paper, a simulation of the folding process, based on a random perturbations of the phi, psi, chi1 dihedral angles, is proposed to approach the formation at the atom level of both principal elements of protein secondary structure, the alpha-helix and the beta-hairpin structures. Expecting to understand what may happen in solution during the formation of such structures, the behaviour of large sets of random conformations that are generated for small oligopeptides was analysed. Different factors that may influence the folding (as conformational propensity, hydrophobic interactions and side-chain mobility) were investigated. The difference between the corresponding theoretical folding and the real conformational diversity that is observed in solution is appraised by a comparison between the calculated and observed NMR secondary chemical shifts. From this study it appears that hydrophobic interactions and mobility represent the principal factors that initiate folding and determine the observed hydrogen-bond pattern, which subsequently allows packing between the peptide side chains. 相似文献
3.
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
4.
We describe a method for predicting the three-dimensional (3-D) structure of proteins from their sequence alone. The method is based on the electrostatic screening model for the stability of the protein main-chain conformation. The free energy of a protein as a function of its conformation is obtained from the potentials of mean force analysis of high-resolution x-ray protein structures. The free energy function is simple and contains only 44 fitted coefficients. The minimization of the free energy is performed by the torsion space Monte Carlo procedure using the concept of hierarchic condensation. The Monte Carlo minimization procedure is applied to predict the secondary, super-secondary, and native 3-D structures of 12 proteins with 28–110 amino acids. The 3-D structures of the majority of local secondary and super-secondary structures are predicted accurately. This result suggests that control in forming the native-like local structure is distributed along the entire protein sequence. The native 3-D structure is predicted correctly for 3 of 12 proteins composed mainly from the α-helices. The method fails to predict the native 3-D structure of proteins with a predominantly β secondary structure. We suggest that the hierarchic condensation is not an appropriate procedure for simulating the folding of proteins made up primarily from β-strands. The method has been proved accurate in predicting the local secondary and super-secondary structures in the blind ab initio 3-D prediction experiment. Proteins 31:74–96, 1998. © 1998 Wiley-Liss, Inc. 相似文献
5.
Ugo Bastolla Helge Frauenkron Erwin Gerstner Peter Grassberger Walter Nadler 《Proteins》1998,32(1):52-66
We demonstrate that the recently proposed pruned-enriched Rosenbluth method (PERM) (Grassberger, Phys. Rev. E 56:3682, 1997) leads to extremely efficient algorithms for the folding of simple model proteins. We test it on several models for lattice heteropolymers, and compare it to published Monte Carlo studies of the properties of particular sequences. In all cases our method is faster than the previous ones, and in several cases we find new minimal energy states. In addition to producing more reliable candidates for ground states, our method gives detailed information about the thermal spectrum and thus allows one to analyze thermodynamic aspects of the folding behavior of arbitrary sequences. Proteins 32:52–66, 1998. © 1998 Wiley-Liss, Inc. 相似文献
6.
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
7.
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
8.
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
9.
An easy and uncomplicated method to predict the solvent accessibility state of a site in a multiple protein sequence alignment is described. The approach is based on amino acid exchange and compositional preference matrices for each of three accessibility states: buried, exposed, and intermediate. Calculations utilized a modified version of the 3D―ali databank, a collection of multiple sequence alignments anchored through protein tertiary structural superpositions. The technique achieves the same accuracy as much more complex methods and thus provides such advantages as computational affordability, facile updating, and easily understood residue substitution patterns useful to biochemists involved in protein engineering, design, and structural prediction. The program is available from the authors; and, due to its simplicity, the algorithm can be readily implemented on any system. For a given alignment site, a hand calculation can yield a comparative prediction. Proteins 32:190–199, 1998. © 1998 Wiley-Liss, Inc. 相似文献
10.
11.
An efficient Monte Carlo (MC) algorithm using concerted backbone rotations is combined with a recently developed implicit membrane model to simulate the folding of the hydrophobic transmembrane domain M2TM of the M2 protein from influenza A virus and Sarcolipin at atomic resolution. The implicit membrane environment is based on generalized Born theory and has been calibrated against experimental data. The MC sampling has previously been used to fold several small polypeptides and been shown to be equivalent to molecular dynamics (MD). In combination with a replica exchange algorithm, M2TM is found to form continuous membrane spanning helical conformations for low temperature replicas. Sarcolipin is only partially helical, in agreement with the experimental NMR structures in lipid bilayers and detergent micelles. Higher temperature replicas exhibit a rapidly decreasing helicity, in agreement with expected thermodynamic behavior. To exclude the possibility of an erroneous helical bias in the simulations, the model is tested by sampling a synthetic Alanine-rich polypeptide of known helicity. The results demonstrate there is no overstabilization of helical conformations, indicating that the implicit model captures the essential components of the native membrane environment for M2TM and Sarcolipin. 相似文献
12.
Since a protein's dynamic fluctuation inside cells affects the protein's biological properties, we present a novel method to study the ensemble of near-native structures (NNS) of proteins, namely, the conformations that are very similar to the experimentally determined native structure. We show that this method enables us to (i) quantify the difficulty of predicting a protein's structure, (ii) choose appropriate simplified representations of protein structures, and (iii) assess the effectiveness of knowledge-based potential functions. We found that well-designed simple representations of protein structures are likely as accurate as those more complex ones for certain potential functions. We also found that the widely used contact potential functions stabilize NNS poorly, whereas potential functions incorporating local structure information significantly increase the stability of NNS. 相似文献
13.
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
14.
The recent determination of crystal structures for several important membrane proteins opens the way for comparative modeling of their membrane-spanning regions. However, the ability to predict correctly the structures of loop regions, which may be critical, for example, in ligand binding, remains a considerable challenge. To meet this challenge, accurate scoring methods have to discriminate between candidate conformations of an unknown loop structure. Some success in loop prediction has been reported for globular proteins; however, the proximity of membrane protein loops to the lipid bilayer casts doubt on the applicability of the same scoring methods to this problem. In this work, we develop \"decoy libraries\" of non-native folds generated, using the structures of two membrane proteins, with molecular dynamics and Monte Carlo techniques over a range of temperatures. We introduce a new approach for decoy library generation by constructing a flat distribution of conformations covering a wide range of Calpha-root-mean-square deviation (RMSD) from the native structure; this removes possible bias in subsequent scoring stages. We then score these decoy conformations with effective energy functions, using increasingly more cpu-intensive implicit solvent models, including (1) simple Coulombic electrostatics with constant or distance-dependent dielectrics; (2) atomic solvation parameters; (3) the effective energy function (EEF1) of Lazaridis and Karplus; (4) generalized Born/Analytical Continuum Solvent; and (5) finite-difference Poisson-Boltzmann energy functions. We show that distinction of native-like membrane protein loops may be achieved using effective energies with the assumption of a homogenous environment; thus, the absence of the adjacent lipid bilayer does not affect the scoring ability. In particular, the Analytical Continuum Solvent and finite-difference Poisson-Boltzmann energy functions are seen to be the most powerful scoring functions. Interestingly, the use of the uncharged states of ionizable sidechains is shown to aid prediction, particularly for the simplest energy functions. 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.
The authors studied the temperature-induced unfolding of ubiquitin by all-atom Monte Carlo simulations. The unfolding behavior is compared with that seen in previous simulations of the mechanical unfolding of this protein, based on the same model. In mechanical unfolding, secondary-structure elements were found to break in a quite well-defined order. In thermal unfolding, the authors saw somewhat larger event-to-event fluctuations, but the unfolding pathway was still far from random. Two long-lived secondary-structure elements could be identified in the simulations. These two elements have been found experimentally to be the thermally most stable ones. Interestingly, one of these long-lived elements, the first beta-hairpin, was found to break early in the mechanical unfolding simulations. Their combined simulation results thus enable the authors to predict in detail important differences between the thermal and mechanical unfolding behaviors of ubiquitin. 相似文献
17.
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
18.
Tatjana Škrbić Trinh X. Hoang Amos Maritan Jayanth R. Banavar Achille Giacometti 《Proteins》2019,87(3):176-184
A phase of matter is a familiar notion for inanimate physical matter. The nature of a phase of matter transcends the microscopic material properties. For example, materials in the liquid phase have certain common properties independent of the chemistry of the constituents: liquids take the shape of the container; they flow; and they can be poured—alcohol, oil, and water as well as a Lennard-Jones computer model exhibit similar behavior when poised in the liquid phase. Here, we identify a hitherto unstudied “phase” of matter, the elixir phase, in a simple model of a polymeric chain whose backbone has the correct local cylindrical symmetry induced by the tangent to the chain. The elixir phase appears on breaking the cylindrical symmetry by adding side spheres along the negative normal direction, as in proteins. This phase, nestled between other phases, has multiple ground states made up of building blocks of helices and almost planar sheets akin to protein native folds. We discuss the similarities of this “phase” of a finite size system to the liquid crystal and spin glass phases. Our findings are relevant for understanding proteins; the creation of novel bioinspired nanomachines; and also may have implications for life elsewhere in the cosmos. 相似文献
19.
We have improved the multiple linear regression (MLR) algorithm for protein secondary structure prediction by combining it with the evolutionary information provided by multiple sequence alignment of PSI-BLAST. On the CB513 dataset, the three states average overall per-residue accuracy, Q(3), reached 76.4%, while segment overlap accuracy, SOV99, reached 73.2%, using a rigorous jackknife procedure and the strictest reduction of eight states DSSP definition to three states. This represents an improvement of approximately 5% on overall per-residue accuracy compared with previous work. The relative solvent accessibility prediction also benefited from this combination of methods. The system achieved 77.7% average jackknifed accuracy for two states prediction based on a 25% relative solvent accessibility mode, with a Mathews' correlation coefficient of 0.548. The improved MLR secondary structure and relative solvent accessibility prediction server is available at http://spg.biosci.tsinghua.edu.cn/. 相似文献
20.
A solvation term based on the solvent accessible surface area (SASA) is combined with the CHARMM polar hydrogen force field for the efficient simulation of peptides and small proteins in aqueous solution. Only two atomic solvation parameters are used: one is negative for favoring the direct solvation of polar groups and the other positive for taking into account the hydrophobic effect on apolar groups. To approximate the water screening effects on the intrasolute electrostatic interactions, a distance-dependent dielectric function is used and ionic side chains are neutralized. The use of an analytical approximation of the SASA renders the model extremely efficient (i.e., only about 50% slower than in vacuo simulations). The limitations and range of applicability of the SASA model are assessed by simulations of proteins and structured peptides. For the latter, the present study and results reported elsewhere show that with the SASA model it is possible to sample a significant amount of folding/unfolding transitions, which permit the study of the thermodynamics and kinetics of folding at an atomic level of detail. 相似文献