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1.
We describe an algorithm which enables us to search the conformational space of the side chains of a protein to identify the global minimum energy combination of side chain conformations as well as all other conformations within a specified energy cutoff of the global energy minimum. The program is used to explore the side chain conformational energy surface of a number of proteins, to investigate how this surface varies with the energy model used to describe the interactions within the system and the rotamer library. Enumeration of the rotamer combinations enables us to directly evaluate the partition function, and thus calculate the side chain contribution to the conformational entropy of the folded protein. An investigation of these conformations and the relationships between them shows that most of the conformations near to the global energy minimum arise from changes in side chain conformations that are essentially independent; very few result from a concerted change in conformation of two or more residues. Some of the limitations of the approach are discussed. Proteins 33:227–239, 1998. © 1998 Wiley-Liss, Inc. 相似文献
2.
Marshall SA Vizcarra CL Mayo SL 《Protein science : a publication of the Protein Society》2005,14(5):1293-1304
Successfully modeling electrostatic interactions is one of the key factors required for the computational design of proteins with desired physical, chemical, and biological properties. In this paper, we present formulations of the finite difference Poisson-Boltzmann (FDPB) model that are pairwise decomposable by side chain. These methods use reduced representations of the protein structure based on the backbone and one or two side chains in order to approximate the dielectric environment in and around the protein. For the desolvation of polar side chains, the two-body model has a 0.64 kcal/mol RMSD compared to FDPB calculations performed using the full representation of the protein structure. Screened Coulombic interaction energies between side chains are approximated with an RMSD of 0.13 kcal/mol. The methods presented here are compatible with the computational demands of protein design calculations and produce energies that are very similar to the results of traditional FDPB calculations. 相似文献
3.
Calculation of the total electrostatic energy of a macromolecular system: solvation energies, binding energies, and conformational analysis 总被引：26，自引：0，他引：26
In this report we describe an accurate numerical method for calculating the total electrostatic energy of molecules of arbitrary shape and charge distribution, accounting for both Coulombic and solvent polarization terms. In addition to the solvation energies of individual molecules, the method can be used to calculate the electrostatic energy associated with conformational changes in proteins as well as changes in solvation energy that accompany the binding of charged substrates. The validity of the method is examined by calculating the hydration energies of acetate, methyl ammonium, ammonium, and methanol. The method is then used to study the relationship between the depth of a charge within a protein and its interaction with the solvent. Calculations of the relative electrostatic energies of crystal and misfolded conformations of Themiste dyscritum hemerythrin and the VL domain of an antibody are also presented. The results indicate that electrostatic charge-solvent interactions strongly favor the crystal structures. More generally, it is found that charge-solvent interactions, which are frequently neglected in protein structure analysis, can make large contributions to the total energy of a macromolecular system. 相似文献
4.
Hydrogen bonding is a key contributor to the specificity of intramolecular and intermolecular interactions in biological systems. Here, we develop an orientation-dependent hydrogen bonding potential based on the geometric characteristics of hydrogen bonds in high-resolution protein crystal structures, and evaluate it using four tests related to the prediction and design of protein structures and protein-protein complexes. The new potential is superior to the widely used Coulomb model of hydrogen bonding in prediction of the sequences of proteins and protein-protein interfaces from their structures, and improves discrimination of correctly docked protein-protein complexes from large sets of alternative structures. 相似文献
5.
Dead-End Based Modeling Tools to Explore the Sequence Space That Is Compatible with a Given Scaffold
The dead-end elimination algorithm has proven to be a powerful tool in protein homology modeling since it allows one to determine rapidly the global minimum-energy conformation (GMEC) of an arbitrarily large collection of side chains, given fixed backbone coordinates. After introducing briefly the necessary background, we focus on logic arguments that increase the efficacy of the dead-end elimination process. Second, we present new theoretical considerations on the use of the dead-end elimination method as a tool to identify sequences that are compatible with a given scaffold structure. Third, we initiate a search for properties derived from the computed GMEC structure to predict whether a given sequence can be well packed in the core of a protein. Three properties will be considered: the nonbonded energy, the accessible surface area, and the extent by which the GMEC side-chain conformations deviate from a locally optimal conformation. 相似文献
6.
Conformational changes of biological macromolecules when binding with ligands have long been observed and remain a challenge for automated docking methods. Here we present a novel protein-ligand docking software called FLIPDock (Flexible LIgand-Protein Docking) allowing the automated docking of flexible ligand molecules into active sites of flexible receptor molecules. In FLIPDock, conformational spaces of molecules are encoded using a data structure that we have developed recently called the Flexibility Tree (FT). While the FT can represent fully flexible ligands, it was initially designed as a hierarchical and multiresolution data structure for the selective encoding of conformational subspaces of large biological macromolecules. These conformational subspaces can be built to span a range of conformations important for the biological activity of a protein. A variety of motions can be combined, ranging from domains moving as rigid bodies or backbone atoms undergoing normal mode-based deformations, to side chains assuming rotameric conformations. In addition, these conformational subspaces are parameterized by a small number of variables which can be searched during the docking process, thus effectively modeling the conformational changes in a flexible receptor. FLIPDock searches the variables using genetic algorithm-based search techniques and evaluates putative docking complexes with a scoring function based on the AutoDock3.05 force-field. In this paper, we describe the concepts behind FLIPDock and the overall architecture of the program. We demonstrate FLIPDock's ability to solve docking problems in which the assumption of a rigid receptor previously prevented the successful docking of known ligands. In particular, we repeat an earlier cross docking experiment and demonstrate an increased success rate of 93.5%, compared to original 72% success rate achieved by AutoDock over the 400 cross-docking calculations. We also demonstrate FLIPDock's ability to handle conformational changes involving backbone motion by docking balanol to an adenosine-binding pocket of protein kinase A. 相似文献
7.
Protein solvation energies are often taken to be proportional to solvent-accessible surface areas. Computation of these areas is numerically demanding and may become a bottleneck for folding and design applications. Fast graph-based methods, such as dead-end elimination (DEE), become possible if all energies, including solvation energies, are expressed as single-residue and pair-residue terms. To this end, Street and Mayo originated a pair-residue approximation for solvent-accessible surface areas (Street AG, Mayo SL. Pairwise calculation of protein solvent accessible surface areas. Fold Des 1998;3:253-258). The dominant source of error in this method is the overlapping burial of side-chain surfaces in the protein core. Here we report a new pair-residue approximation, which greatly reduces this overlap error by the use of optimized generic side-chains. We have tested the generic-side-chain method for the ten proteins studied by Street and Mayo and for 377 single-domain proteins from the CATH database (Orengo CA, Michie AD, Jones S, Jones DT, Swindells MB, Thornton JM. CATH-A hierarchic classification of protein domain structures. Structure 1997;5:1093-1108). With little additional cost in computation, the new method consistently reduces error for total areas and residue-by-residue areas by more than a factor of two. For example, the residue-by-residue error (for buried area) is reduced from 7.42 A(2) to 3.70 A(2). This difference translates into a solvation energy difference of approximately 0.2 kcal/mol per residue, amounting to a reduction in root-mean-square energy error of 2 kcal/mol for a 100 residue chain, a potentially critical difference for both protein folding and design applications. 相似文献
8.
Peroxisomes are small subcellular compartments responsible for a range of essential metabolic processes. Efforts in predicting peroxisomal protein import are challenged by species variation and sparse sequence data sets with experimentally confirmed localization. We present a predictor of peroxisomal import based on the presence of the dominant peroxisomal targeting signal one (PTS1), a seemingly wellconserved but highly unspecific motif. The signal appears to rely on subtle dependencies with the preceding residues. We evaluate prediction accuracies against two alternative predictor services, PEROXIP and the PTS1 PREDICTOR. We test the integrity of prediction on a range of prokaryotic and eukaryotic proteomes lacking peroxisomes. Similarly we test the accuracy on peroxisomal proteins known to not overlap with training data. The model identified a number of proteins within the RIKEN IPS7 mouse protein dataset as potentially novel peroxisomal proteins. Three were confirmed in vitro using immunofluorescent detection of myc-epitope-tagged proteins in transiently transfected BHK-21 cells (Dhrs2, Serhl, and Ehhadh). The final model has a superior specificity to both alternatives, and an accuracy better than PEROXIP and on par with PTS1 PREDICTOR. Thus, the model we present should prove invaluable for labeling PTS1 targeted proteins with high confidence. We use the predictor to screen several additional eukaryotic genomes to revise previously estimated numbers of peroxisomal proteins. Available at http://pprowler.itee.uq.edu.au. 相似文献
9.
10.
Ross SA Sarisky CA Su A Mayo SL 《Protein science : a publication of the Protein Society》2001,10(2):450-454
The solution structures of two computationally designed core variants of the beta 1 domain of streptococcal protein G (G beta 1) were solved by (1)H NMR methods to assess the robustness of amino acid sequence selection by the ORBIT protein design package under changes in protein backbone specification. One variant has mutations at three of 10 core positions and corresponds to minimal perturbations of the native G beta 1 backbone. The other, with mutations at six of 10 positions, was calculated for a backbone in which the separation between G beta 1's alpha-helix and beta-sheet was increased by 15% relative to native G beta 1. Exchange broadening of some resonances and the complete absence of others in spectra of the sixfold mutant bespeak conformational heterogeneity in this protein. The NMR data were sufficiently abundant, however, to generate structures of similar, moderately high quality for both variants. Both proteins adopt backbone structures similar to their target folds. Moreover, the sequence selection algorithm successfully predicted all core chi(1) angles in both variants, five of six chi(2) angles in the threefold mutant and four of seven chi(2) angles in the sixfold mutant. We conclude that ORBIT calculates sequences that fold specifically to a geometry close to the template, even when the template is moderately perturbed relative to a naturally occurring structure. There are apparently limits to the size of acceptable perturbations: In this study, the larger perturbation led to undesired dynamic behavior. 相似文献
11.
Interest centers here on whether the use of a fixed charge distribution of a protein solute, or a treatment that considers proton-binding equilibria by solving the Poisson equation, is a better approach to discriminate native from non-native conformations of proteins. In this analysis of the charge distribution of 7 proteins, we estimate the solvation free energy contribution to the total free energy by exploring the 2(zeta) possible ionization states of the whole molecule, with zeta being the number of ionizable groups in the amino acid sequence, for every conformation in the ensembles of 7 proteins. As an additional consideration of the role of electrostatic interactions in determining the charge distribution of native folds, we carried out a comparison of alternative charge assignment models for the ionizable residues in a set of 21 native-like proteins. The results of this work indicate that (1) for 6 out of 7 proteins, estimation of solvent polarization based on the Generalized Born model with a fixed charge distribution provides the optimal trade-off between accuracy, with respect to the Poisson equation, and speed when compared to the accessible surface area model; for the seventh protein, consideration of all possible ionization states of the whole molecule appears to be crucial to discriminate the native from non-native conformations; (2) significant differences in the degree of ionization and hence the charge distribution for native folds are found between the different charge models examined; (3) the stability of the native state is determined by a delicate balance of all the energy components, and (4) conformational entropy, and hence the dynamics of folding, may play a crucial role for a successful ab initio protein folding prediction. 相似文献
12.
V. Helms J. A. McCammon 《Protein science : a publication of the Protein Society》1997,6(11):2336-2343
Protein function is often controlled by ligand-induced conformational transitions. Yet, in spite of the increasing number of three-dimensional crystal structures of proteins in different conformations, not much is known about the driving forces of these transitions. As an initial step toward exploring the conformational and energetic landscape of protein kinases by computational methods, intramolecular energies and hydration free energies were calculated for different conformations of the catalytic domain of cAMP-dependent protein kinase (cAPK) with a continuum (Poisson) model for the electrostatics. Three protein kinase crystal structures for ternary complexes of cAPK with the peptide inhibitor PKI(5-24) and ATP or AMP-PNP were modeled into idealized intermediate and open conformations. Concordant with experimental observation, we find that the binding of PKI(5-24) is more effective in stabilizing the closed and intermediate forms of cAPK than ATP. PKI(5-24) seems to drive the final closure of the active site cleft from intermediate to closed state because ATP does not distinguish between these two states. Binding of PKI(5-24) and ATP is energetically additive. 相似文献
13.
Solvation effects play a profound role in the energetics of protein folding. While a continuum dielectric model of solvation may provide a sufficiently accurate estimate of the solvation effects, until now this model was too computationally expensive and unstable for folding simulations. Here we proposed a fast yet accurate and robust implementation of the boundary element solution of the Poisson equation, the REBEL algorithm. Using our earlier double‐energy scheme, we included for the first time the mathematically rigorous continuous REBEL solvation term in our Biased Probability Monte Carlo (BPMC) simulations of the peptide folding. The free energy of a 23‐residue ββα‐peptide was then globally optimized with and without the solvation electrostatics contribution. An ensemble of ββα conformations was found at and near the global minimum of the energy function with the REBEL electrostatic solvation term. Much poorer correspondence to the native solution structure was found in the “control” simulations with a traditional method to account for solvation via a distance‐dependent dielectric constant. Each simulation took less than 40 h (21 h without electrostatic solvation calculation) on a single Alpha 677 MHz CPU and involved more than 40,000 solvation energy evaluations. This work demonstrates for the first time that such a simulation can be performed in a realistic time frame. The proposed procedure may eliminate the energy evaluation accuracy bottleneck in folding simulations. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 60: 124–133, 2001 相似文献
14.
Side chain prediction is an integral component of computational antibody design and structure prediction. Current antibody modelling tools use backbone‐dependent rotamer libraries with conformations taken from general proteins. Here we present our antibody‐specific rotamer library, where rotamers are binned according to their immunogenetics (IMGT) position, rather than their local backbone geometry. We find that for some amino acid types at certain positions, only a restricted number of side chain conformations are ever observed. Using this information, we are able to reduce the breadth of the rotamer sampling space. Based on our rotamer library, we built a side chain predictor, position‐dependent antibody rotamer swapper (PEARS). On a blind test set of 95 antibody model structures, PEARS had the highest average χ1 and accuracy (78.7% and 64.8%) compared to three leading backbone‐dependent side chain predictors. Our use of IMGT position, rather than backbone ϕ/ψ, meant that PEARS was more robust to errors in the backbone of the model structure. PEARS also achieved the lowest number of side chain–side chain clashes. PEARS is freely available as a web application at http://opig.stats.ox.ac.uk/webapps/pears . 相似文献
15.
R. Tanimura A. Kidera H. Nakamura 《Protein science : a publication of the Protein Society》1994,3(12):2358-2365
The problem of protein side-chain packing for a given backbone trace is investigated using 3 different prediction models. The first requires an exhaustive search of all possible combinations of side-chain conformers, using the dead-end elimination theorem. The second considers only side-chain-backbone interactions, whereas the third neglects side-chain-backbone interactions and instead keeps side-chain-side-chain interactions. Predictions of side-chain conformations for 11 proteins using all 3 models show that removal of side-chain-side-chain interactions does not cause a large decrease in the prediction accuracy, whereas the model having only side-chain-side-chain interactions still retains a significant level of accuracy. These results suggest that the 2 classes of interactions, side-chain-backbone and side-chain-side-chain, are consistent with each other and work concurrently to stabilize the native conformations. This is confirmed by analyses of energy spectra of the side-chain conformations derived from the fourth prediction model, the Independent model, which gives almost the same quality of the prediction as the dead-end elimination. The analyses indicate that the 2 classes of interactions simultaneously increase the energy difference between the native and nonnative conformations. 相似文献
16.
17.
Brian N. Dominy 《Molecular simulation》2013,39(4-6):259-274
Abstract As the field of theoretical biophysics begins to recognize systems of longer timescales and larger magnitude, rapid approaches for investigating these systems are required. One promising simplification of the typical system of a solute surrounded by water is the use of implicit solvation models. The generalized Born implicit solvent offers a rapid approach for computing the electrostatic effects of bulk solvent without the explicit representation of water molecules. This report describes the parameterization of a generalized Born (GB) model for protein and nucleic acid structures. As a demonstration of the usefulness of this approach, the GB model is applied toward the discrimination of misfolded and properly folded protein structures. This study attempts to illustrate the potential of the GB model for molecular dynamics simulations over longer timescales as well as for screening large structural databases. 相似文献
18.
We present a computational approach for predicting structures of ligand-protein complexes and analyzing binding energy landscapes that combines Monte Carlo simulated annealing technique to determine the ligand bound conformation with the dead-end elimination algorithm for side-chain optimization of the protein active site residues. Flexible ligand docking and optimization of mobile protein side-chains have been performed to predict structural effects in the V32I/I47V/V82I HIV-1 protease mutant bound with the SB203386 ligand and in the V82A HIV-1 protease mutant bound with the A77003 ligand. The computational structure predictions are consistent with the crystal structures of these ligand-protein complexes. The emerging relationships between ligand docking and side-chain optimization of the active site residues are rationalized based on the analysis of the ligand-protein binding energy landscape. Proteins 33:295–310, 1998. © 1998 Wiley-Liss, Inc. 相似文献
19.
Structure prediction and computational protein design should benefit from accurate solvent models. We have applied implicit solvent models to two problems that are central to this area. First, we performed sidechain placement for 29 proteins, using a solvent model that combines a screened Coulomb term with an Accessible Surface Area term (CASA model). With optimized parameters, the prediction quality is comparable with earlier work that omitted electrostatics and solvation altogether. Second, we computed the stability changes associated with point mutations involving ionized sidechains. For over 1000 mutations, including many fully or partly buried positions, we compared CASA and two generalized Born models (GB) with a more accurate model, which solves the Poisson equation of continuum electrostatics numerically. CASA predicts the correct sign and order of magnitude of the stability change for 81% of the mutations, compared to 97% with the best GB. We also considered 140 mutations for which experimental data are available. Comparing to experiment requires additional assumptions about the unfolded protein structure, protein relaxation in response to the mutations, and contributions from the hydrophobic effect. With a simple, commonly-used unfolded state model, the mean unsigned error is 2.1 kcal/mol with both CASA and the best GB. Overall, the electrostatic model is not important for sidechain placement; CASA and GB are equivalent for surface mutations, while GB is far superior for fully or partly buried positions. Thus, for problems like protein design that involve all these aspects, the most recent GB models represent an important step forward. Along with the recent discovery of efficient, pairwise implementations of GB, this will open new possibilities for the computational engineering of proteins. 相似文献
20.
Jackson RM 《Protein science : a publication of the Protein Society》1999,8(3):603-613
The protein-protein interaction energy of 12 nonhomologous serine protease-inhibitor and 15 antibody-antigen complexes is calculated using a molecular mechanics formalism and dissected in terms of the main-chain vs. side-chain contribution, nonrotameric side-chain contributions, and amino acid residue type involvement in the interface interaction. There are major differences in the interactions of the two types of protein-protein complex. Protease-inhibitor complexes interact predominantly through a main-chain-main-chain mechanism while antibody-antigen complexes interact predominantly through a side-chain-side-chain or a side-chain-main-chain mechanism. However, there is no simple correlation between the main-chain-main-chain interaction energy and the percentage of main-chain surface area buried on binding. The interaction energy is equally effected by the presence of nonrotameric side-chain conformations, which constitute approximately 20% of the interaction energy. The ability to reproduce the interface interaction energy of the crystal structure if original side-chain conformations are removed from the calculation is much greater in the protease-inhibitor complexes than the antibody-antigen complexes. The success of a rotameric model for protein-protein docking appears dependent on the extent of the main-chain-main-chain contribution to binding. Analysis of (1) residue type and (2) residue pair interactions at the interface show that antibody-antigen interactions are very restricted with over 70% of the antibody energy attributable to just six residue types (Tyr > Asp > Asn > Ser > Glu > Trp) in agreement with previous studies on residue propensity. However, it is found here that 50% of the antigen energy is attributable to just four residue types (Arg = Lys > Asn > Asp). On average just 12 residue pair interactions (6%) contribute over 40% of the favorable interaction energy in the antibody-antigen complexes, with charge-charge and charge/polar-tyrosine interactions being prominent. In contrast protease inhibitors use a diverse set of residue types and residue pair interactions. 相似文献