首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献,搜索用时 15 毫秒
1.
We present design details and first tests of a new evolutionary algorithm approach to ab initio protein folding. It does not focus on dihedral angles exclusively, but mainly operates on introduction, extension, break-up, and destruction of secondary structure elements, given as correlated dihedral angle values. In first test applications to polyalanines (up to 60 residues) and random primary sequences (up to 40 residues), we demonstrate that this use of prior knowledge is well balanced: On the one hand, it ensures quick introduction of secondary structure elements if they are favorable for a given primary sequence, but still allows for efficient location of pure random coil solutions without enforcing any secondary structure elements, if folds of this type are preferred by the given primary sequence. Furthermore, the algorithm is clearly able to pack several secondary structure elements into favorable tertiary structure arrangements, although no part of the algorithm is explicitly designed to do this. In first test examples on real-life peptides between 21 and 44 residues from the Protein Data Bank, the quality of the results depends on the force field used (as expected); nevertheless, we can show that the algorithm is able to find structures in good agreement with the targets easily and consistently, if the force field allows for that.  相似文献   

2.
3.
4.
De novo and inverse folding predictions of protein structure and dynamics   总被引:6,自引:0,他引:6  
Summary In the last two years, the use of simplified models has facilitated major progress in the globular protein folding problem, viz., the prediction of the three-dimensional (3D) structure of a globular protein from its amino acid sequence. A number of groups have addressed the inverse folding problem where one examines the compatibility of a given sequence with a given (and already determined) structure. A comparison of extant inverse protein-folding algorithms is presented, and methodologies for identifying sequences likely to adopt identical folding topologies, even when they lack sequence homology, are described. Extension to produce structural templates or fingerprints from idealized structures is discussed, and for eight-membered β-barrel proteins, it is shown that idealized fingerprints constructed from simple topology diagrams can correctly identify sequences having the appropriate topology. Furthermore, this inverse folding algorithm is generalized to predict elements of supersecondary structure including β-hairpins, helical hairpins and α/β/α fragments. Then, we describe a very high coordination number lattice model that can predict the 3D structure of a number of globular proteins de novo; i.e. using just the amino acid sequence. Applications to sequences designed by DeGrado and co-workers [Biophys. J., 61 (1992) A265] predict folding intermediates, native states and relative stabilities in accord with experiment. The methodology has also been applied to the four-helix bundle designed by Richardson and co-workers [Science, 249 (1990) 884] and a redesigned monomeric version of a naturally occurring four-helix dimer, rop. Based on comparison to the rop dimer, the simulations predict conformations with rms values of 3–4 ? from native. Furthermore, the de novo algorithms can asses the stability of the folds predicted from the inverse algorithm, while the inverse folding algorithms can assess the quality of the de novo models. Thus, the synergism of the de novo and inverse folding algorthhm approaches provides a set of complementary tools that will facilitate further progress on the protein-folding problem.  相似文献   

5.
Determination of the native state of a protein from its amino acid sequence is the goal of protein folding simulations, with potential applications in gene therapy and drug design. Location of the global minimum structure for a given sequence, however, is a difficult optimisation problem. In this paper, we describe the development and application of a genetic algorithm (GA) to find the lowest-energy conformations for the 2D HP lattice bead protein model. Optimisation of the parameters of our standard GA program reveals that the GA is most successful (at finding the lowest-energy conformations) for high rates of mating and mutation and relatively high elitism. We have also introduced a number of new genetic operators: a duplicate predator—which maintains population diversity by eliminating duplicate structures; brood selection—where two parent structures undergo crossover and give rise to a brood of (not just two) offspring; and a Monte Carlo based local search algorithm—to explore the neighbourhood of all members of the population. It is shown that these operators lead to significant improvements in the success and efficiency of the GA, both compared with our standard GA and with previously published GA studies for benchmark HP sequences with up to 50 beads.  相似文献   

6.
An automatic procedure is proposed for reconstruction of a protein backbone from its C(alpha)-trace; it is based on optimization of a simplified energy function of a peptide backbone, given its alpha-carbon trace. The energy is expressed as a sum of the energies of interaction between backbone peptide groups that are not neighbors in the sequence, the energies of local interactions within all amino acid residues, and a harmonic penalty function accounting for the conservation of standard bond angles. The energy of peptide group interactions is calculated using the assumption that each peptide group acts as a point dipole. For local interaction energy, use is made of a two-dimensional Fourier series expansion of the energies of model terminally blocked amino acid residues, calculated with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field in the angles lambda((1)) and lambda((2)) defining the rotation of peptide groups adjacent to a C(alpha) carbon atom about the corresponding C(alpha) em leader C(alpha) virtual-bond axes. To explore all possible rotations of peptide groups within a fixed C(alpha)-trace, a Monte Carlo search is carried out. The initial lambda angles are calculated by aligning the dipoles of the peptide groups that are close in space, subject to the condition of favorable local interactions. After the Monte Carlo search is accomplished with the simplified energy function, the energy of the structure is minimized with the ECEPP/3 force field, with imposition of distance constraints corresponding to the initial C(alpha)-trace geometry. The procedure was tested on model alpha-helices and beta-sheets, as well as on the crystal structure of the immunoglobulin binding protein (PDB code: 1IGD, an alpha/beta protein). In all cases, complete backbone geometry was reconstructed with a root-mean-square (rms) deviation of 0.5 A from the all-atom target structure.  相似文献   

7.
The ability to predict protein folding rates constitutes an important step in understanding the overall folding mechanisms. Although many of the prediction methods are structure based, successful predictions can also be obtained from the sequence. We developed a novel method called prediction of protein folding rates (PPFR), for the prediction of protein folding rates from protein sequences. PPFR implements a linear regression model for each of the mainstream folding dynamics including two-, multi-, and mixed-state proteins. The proposed method provides predictions characterized by strong correlations with the experimental folding rates, which equal 0.87 for the two- and multistate proteins and 0.82 for the mixed-state proteins, when evaluated with out-of-sample jackknife test. Based on in-sample and out-of-sample tests, the PPFR's predictions are shown to be better than most of other sequence only and structure-based predictors and complementary to the predictions of the most recent sequence-based QRSM method. We show that simultaneous incorporation of several characteristics, including the sequence, physiochemical properties of residues, and predicted secondary structure provides improved quality. This hybridized prediction model was analyzed to reveal the complementary factors that can be used in tandem to predict folding rates. We show that bigger proteins require more time for folding, higher helical and coil content and the presence of Phe, Asn, and Gln may accelerate the folding process, the inclusion of Ile, Val, Thr, and Ser may slow down the folding process, and for the two-state proteins increased beta-strand content may decelerate the folding process. Finally, PPFR provides strong correlation when predicting sequences with low similarity.  相似文献   

8.
A flexible ligand docking protocol based on evolutionary algorithms is investigated. The proposed approach incorporates family competition and adaptive rules to integrate decreasing‐based mutations and self‐adaptive mutations to act as global and local search strategies, respectively. The method is applied to a dihydrofolate reductase enzyme with the anticancer drug methotrexate and two analogues of antibacterial drug trimethoprim. Conformations and orientations closed to the crystallographically determined structures are obtained, as well as alternative structures with low energy. Numerical results indicate that the new approach is very robust. The docked lowest‐energy structures have root‐mean‐square derivations ranging from 0.67 to 1.96 Å with respect to the corresponding crystal structures. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 988–998, 2000  相似文献   

9.
10.
Thede novo protein albebetin has been engineered (J. Mol. Biol. 1992,225, 927–931) to form a predesigned tertiary fold that has not yet been observed in natural proteins. Analysis of albebetin expressed in a cell-free system and inEscherichia coli revealed its compactness, relative stability, and the secondary structure close to the predesigned one. The blast-transforming biological activity of human interferon was grafted to albebetin by attachment of an eight amino acid interferon fragment to the N-terminus of albebetin next to its first methionine residue. The chimeric protein was expressed in a wheat germ cell-free translation system and tested for its structural properties, receptor binding, and biological activity. According to the tests, albebetin incorporating the active interferon fragment has a compact and relatively stable structure, and binds the murine thymocyte recep or effectively. It activates the blast transformation reaction of thymo yte cells even more efficiently than human interferon at low concentrations.  相似文献   

11.
12.
Topology-based interaction potentials are simplified models that use the native contacts in the folded structure of a protein to define an energetically unfrustrated folding funnel. They have been widely used to analyze the folding transition and pathways of different proteins through computer simulations. Obviously, they need a reliable, experimentally determined folded structure to define the model interactions. In structures elucidated through NMR spectroscopy, a complex treatment of the raw experimental data usually provides a series of models, a set of different conformations compatible with the available experimental data. Here, we use an efficient coarse-grained simulation technique to independently consider the contact maps from every different NMR model in a protein whose structure has been resolved by the use of NMR spectroscopy. For lambda-Cro repressor, a homodimeric protein, we have analyzed its folding characteristics with a topology-based model. We have focused on the competition between the folding of the individual chains and their binding to form the final quaternary structure. From 20 different NMR models, we find a predominant three-state folding behavior, in agreement with experimental data on the folding pathway for this protein. Individual NMR models, however, show distinct characteristics, which are analyzed both at the level of the interplay between tertiary/quaternary structure formation and also regarding the thermal stability of the tertiary structure of every individual chain.  相似文献   

13.
Single-molecule spectroscopy is an important new approach for studying the intrinsically heterogeneous process of protein folding. This Review illustrates how different single-molecule fluorescence techniques have improved our understanding of mechanistic aspects in protein folding, exemplified by a series of recent experiments on a small protein.  相似文献   

14.
15.
Routine structure prediction of new folds is still a challenging task for computational biology. The challenge is not only in the proper determination of overall fold but also in building models of acceptable resolution, useful for modeling the drug interactions and protein-protein complexes. In this work we propose and test a comprehensive approach to protein structure modeling supported by sparse, and relatively easy to obtain, experimental data. We focus on chemical shift-based restraints from NMR, although other sparse restraints could be easily included. In particular, we demonstrate that combining the typical NMR software with artificial intelligence-based prediction of secondary structure enhances significantly the accuracy of the restraints for molecular modeling. The computational procedure is based on the reduced representation approach implemented in the CABS modeling software, which proved to be a versatile tool for protein structure prediction during the CASP (CASP stands for critical assessment of techniques for protein structure prediction) experiments (see http://predictioncenter/CASP6/org). The method is successfully tested on a small set of representative globular proteins of different size and topology, including the two CASP6 targets, for which the required NMR data already exist. The method is implemented in a semi-automated pipeline applicable to a large scale structural annotation of genomic data. Here, we limit the computations to relatively small set. This enabled, without a loss of generality, a detailed discussion of various factors determining accuracy of the proposed approach to the protein structure prediction.  相似文献   

16.
By using distributed computing techniques and a supercluster of more than 20,000 processors we simulated folding of a 20-residue Trp Cage miniprotein in atomistic detail with implicit GB/SA solvent at a variety of solvent viscosities (gamma). This allowed us to analyze the dependence of folding rates on viscosity. In particular, we focused on the low-viscosity regime (values below the viscosity of water). In accordance with Kramers' theory, we observe approximately linear dependence of the folding rate on 1/gamma for values from 1-10(-1)x that of water viscosity. However, for the regime between 10(-4)-10(-1)x that of water viscosity we observe power-law dependence of the form k approximately gamma(-1/5). These results suggest that estimating folding rates from molecular simulations run at low viscosity under the assumption of linear dependence of rate on inverse viscosity may lead to erroneous results.  相似文献   

17.
18.
19.
20.
One of the most important challenges in computational and molecular biology is to understand the relationship between amino acid sequences and the folding rates of proteins. Recent works suggest that topological parameters, amino acid properties, chain length and the composition index relate well with protein folding rates, however, sequence order information has seldom been considered as a property for predicting protein folding rates. In this study, amino acid sequence order was used to derive an effective method, based on an extended version of the pseudo-amino acid composition, for predicting protein folding rates without any explicit structural information. Using the jackknife cross validation test, the method was demonstrated on the largest dataset (99 proteins) reported. The method was found to provide a good correlation between the predicted and experimental folding rates. The correlation coefficient is 0.81 (with a highly significant level) and the standard error is 2.46. The reported algorithm was found to perform better than several representative sequence-based approaches using the same dataset. The results indicate that sequence order information is an important determinant of protein folding rates.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号