共查询到20条相似文献，搜索用时 15 毫秒
1.
Faraldo-Gómez JD Forrest LR Baaden M Bond PJ Domene C Patargias G Cuthbertson J Sansom MS 《Proteins》2004,57(4):783-791
In the current report, we provide a quantitative analysis of the convergence of the sampling of conformational space accomplished in molecular dynamics simulations of membrane proteins of duration in the order of 10 nanoseconds. A set of proteins of diverse size and topology is considered, ranging from helical pores such as gramicidin and small beta-barrels such as OmpT, to larger and more complex structures such as rhodopsin and FepA. Principal component analysis of the C(alpha)-atom trajectories was employed to assess the convergence of the conformational sampling in both the transmembrane domains and the whole proteins, while the time-dependence of the average structure was analyzed to obtain single-domain information. The membrane-embedded regions, particularly those of small or structurally simple proteins, were found to achieve reasonable convergence. By contrast, extra-membranous domains lacking secondary structure are often markedly under-sampled, exhibiting a continuous structural drift. This drift results in a significant imprecision in the calculated B-factors, which detracts from any quantitative comparison to experimental data. In view of such limitations, we suggest that similar analyses may be valuable in simulation studies of membrane protein dynamics, in order to attach a level of confidence to any biologically relevant observations. 相似文献
2.
Collective motions in proteins: a covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations. 总被引：13，自引：0，他引：13
A method is described for identifying collective motions in proteins from molecular dynamics trajectories or normal mode simulations. The method makes use of the covariances of atomic positional fluctuations. It is illustrated by an analysis of the bovine pancreatic trypsin inhibitor. Comparison of the covariance and cross-correlation matrices shows that the relative motions have many similar features in the different simulations. Many regions of the protein, especially regions of secondary structure, move in a correlated manner. Anharmonic effects, which are included in the molecular dynamics simulations but not in the normal analysis, are of some importance in determining the larger scale collective motions, but not the more local fluctuations. Comparisons of molecular dynamics simulations in the present and absence of solvent indicate that the environment is of significance for the long-range motions. 相似文献
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Elastic network models (ENMs) are a class of simple models intended to represent the collective motions of proteins. In contrast to all‐atom molecular dynamics simulations, the low computational investment required to use an ENM makes them ideal for speculative hypothesis‐testing situations. Historically, ENMs have been validated via comparison to crystallographic B‐factors, but this comparison is relatively low‐resolution and only tests the predictions of relative flexibility. In this work, we systematically validate and optimize a number of ENM‐type models by quantitatively comparing their predictions to microsecond‐scale all‐atom simulations of three different G protein coupled receptors. We show that, despite their apparent simplicity, well‐optimized ENMs perform remarkably well, reproducing the protein fluctuations with an accuracy comparable to what one would expect from all‐atom simulations run for several hundred nanoseconds. Proteins 2010. © 2010 Wiley‐Liss, Inc. 相似文献
5.
A molecular dynamics study of pig heart citrate synthase is presented that aims to directly address the question of whether, for this enzyme, the ligand-induced closed domain conformation is accessible to the open unliganded enzyme. The approach utilises the technique of essential dynamics sampling, which is used in two modes. In exploring mode, the enzyme is encouraged to explore domain conformations it might not normally sample in free molecular dynamics simulation. In targeting mode, the enzyme is encouraged to adopt the domain conformation of a target structure. Using both modes extensively, it has been found that when the enzyme is prepared from a crystallographic open-domain structure and is in the unliganded state, it is unable to adopt the crystallographic closed-domain conformation of the liganded enzyme. Likewise, when the enzyme is prepared from the crystallographic closed liganded conformation with the ligands removed, it is unable to adopt the crystallographic open domain conformation. Structural investigations point to a common structural difference that is the source of this energy barrier; namely, the shift of alpha-helix 328-341 along its own axis relative to the large domain. Without this shift, the domains are unable to close or open fully. The charged substrate, oxaloacetate, binds near the base of this helix in the large domain and the interaction of Arg329 at the base of the helix with oxaloacetate is one that is consistent with the shift of this helix in going from the crystallographic open to closed structure. Therefore, the results suggest that without the substrate the enzyme remains in a partially open conformation ready to receive the substrate. In this way, the efficiency of the enzyme should be increased over one that is closed part of the time, with its binding site inaccessible to the substrate. 相似文献
6.
The vascular endothelial growth factor (VEGF) seems to be the most important regulator of physiological and pathological angiogenesis, being, for this reason, a favorite target for therapies against angiogenesis-related diseases. VEGF is a homodimer in which the monomers are formed by beta-strands interconnected on the poles by three loops. A recent work showed that an intimate relationship between loops-1 and -3 is required for high affinity binding to the receptors (Kiba et al., J Biol Chem 2003;278:13453-13461). In this work, we report the results of a 10-ns molecular dynamics simulation of VEGF. We analyzed the dynamical behavior of the protein (using a dynamical cross-correlation map) and found that it is governed by a high degree of correlation between the motions of the loops. We also performed a principal component analysis and found an overall motion in which the opposite poles are projected against each other, just like the movement of the wings of a butterfly. From the biological point of view, it is likely that this motion would facilitate receptor binding since VEGF must enter a restricted cavity formed by the two subunits of the receptor. 相似文献
7.
An efficient new method is presented for the characterization of motional correlations derived from a set of protein structures without requiring the separation of overall and internal motion. In this method, termed isotropically distributed ensemble (IDE) analysis, each structure is represented by an ensemble of isotropically distributed replicas corresponding to the situation found in an isotropic protein solution. This leads to a covariance matrix of the cartesian atomic positions with elements proportional to the ensemble average of scalar products of the position vectors with respect to the center of mass. Diagonalization of the covariance matrix yields eigenmodes and amplitudes that describe concerted motions of atoms, including overall rotational and intramolecular dynamics. It is demonstrated that this covariance matrix naturally distinguishes between \"rigid\" and \"mobile\" parts without necessitating a priori selection of a reference structure and an atom set for the orientational alignment process. The method was applied to the analysis of a 5-ns molecular dynamics trajectory of native ubiquitin and a 40-ns trajectory of a partially folded state of ubiquitin. The results were compared with essential dynamics analysis. By taking advantage of the spherical symmetry of the IDE covariance matrix, more than a 10-fold speed up is achieved for the computation of eigenmodes and mode amplitudes. IDE analysis is particularly suitable for studying the correlated dynamics of flexible and large molecules. 相似文献
8.
The molecular chaperone, GroEL, essential for correct protein folding in E. coli, is composed of 14 identical subunits organized in two interacting rings, each providing a folding chamber for non‐native substrate proteins. The oligomeric assembly shows positive cooperativity within each ring and negative cooperativity between the rings. Although it is well known that ATP and long‐range allosteric interactions drive the functional cycle of GroEL, an atomic resolution view of how ligand binding modulates conformational adaptations over long distances remains a major challenge. Moreover, little is known on the relation between equilibrium dynamics at physiological temperatures and the allosteric transitions in GroEL. Here we present multiple all‐atom molecular dynamics simulations of the GroEL‐GroES assemblies at different stages of the functional cycle. Combined with an extensive analysis of the complete set of experimentally available structures, principal component analysis and conformer plots, we provide an explicit evaluation of the accessible conformational space of unliganded GroEL. Our results suggest the presence of pre‐existing conformers at the equatorial domain level, and a shift of the conformational ensemble upon ATP‐binding. At the inter‐ring interface the simulations capture a remarkable offset motion of helix D triggered by ATP‐binding to the folding active ring. The reorientation of helix D, previously only observed upon GroES association, correlates with a change of the internal dynamics in the opposite ring. This work contributes to the understanding of the molecular mechanisms in GroEL and highlights the ability of all‐atom MD simulations to model long‐range structural changes and allosteric events in large systems. Proteins 2012;. © 2012 Wiley Periodicals, Inc. 相似文献
9.
We have investigated energy landscape of human lysozyme in its native state by using principal component analysis and a model, jumping-among-minima (JAM) model. These analyses are applied to 1 nsec molecular dynamics trajectory of the protein in water. An assumption embodied in the JAM model allows us to divide protein motions into intra-substate and inter-substate motions. By examining intra-substate motions, it is shown that energy surfaces of individual conformational substates are nearly harmonic and mutually similar. As a result of principal component analysis and JAM model analysis, protein motions are shown to consist of three types of collective modes, multiply hierarchical modes, singly hierarchical modes, and harmonic modes. Multiply hierarchical modes, the number of which accounts only for 0.5% of all modes, dominate contributions to total mean-square atomic fluctuation. Inter-substate motions are observed only in a small-dimensional subspace spanned by the axes of multiplyhierarchical and singly hierarchical modes. Inter-substate motions have two notable time components: faster component seen within 200 psec and slower component. The former involves transitions among the conformational substates of the low-level hierarchy, whereas the latter involves transitions of the higher level substates observed along the first four multiply hierarchical modes. We also discuss dependence of the subspace, which contains conformational substates, on time duration of simulation. Proteins 33:496–517, 1998. © 1998 Wiley-Liss, Inc. 相似文献
10.
Moitrayee Bhattacharyya Amit Ghosh Priti Hansia Saraswathi Vishveshwara 《Proteins》2010,78(3):506-517
The interdependence of the concept of allostery and enzymatic catalysis, and they being guided by conformational mobility is gaining increased prominence. However, to gain a molecular level understanding of allostery and hence of enzymatic catalysis, it is of utter importance that the networks of amino acids participating in allostery be deciphered. Our lab has been exploring the methods of network analysis combined with molecular dynamics simulations to understand allostery at molecular level. Earlier we had outlined methods to obtain communication paths and then to map the rigid/flexible regions of proteins through network parameters like the shortest correlated paths, cliques, and communities. In this article, we advance the methodology to estimate the conformational populations in terms of cliques/communities formed by interactions including the side‐chains and then to compute the ligand‐induced population shift. Finally, we obtain the free‐energy landscape of the protein in equilibrium, characterizing the free‐energy minima accessed by the protein complexes. We have chosen human tryptophanyl‐tRNA synthetase (hTrpRS), a protein responsible for charging tryptophan to its cognate tRNA during protein biosynthesis for this investigation. This is a multidomain protein exhibiting excellent allosteric communication. Our approach has provided valuable structural as well as functional insights into the protein. The methodology adopted here is highly generalized to illuminate the linkage between protein structure networks and conformational mobility involved in the allosteric mechanism in any protein with known structure. Proteins 2010. © 2009 Wiley‐Liss, Inc. 相似文献
11.
Understanding X-ray crystallographic diffuse scattering is likely to improve our comprehension of equilibrium collective protein dynamics. Here, using molecular dynamics (MD) simulation, a detailed analysis is performed of the origins of diffuse scattering in crystalline Staphylococcal nuclease, for which the complete diffuse scattering pattern has been determined experimentally. The hydrogen-atom contribution and the scattering range over which the scattering can be considered to be a sum of solvent and protein scattering are determined. Two models of correlated protein motion are investigated by calculating the model-derived diffuse scattering and comparing with the scattering calculated directly from MD trajectories. In one model, previously used in diffuse scattering interpretation, the atomic displacement correlations decay isotropically with increasing separation. Model correlation lengths are obtained by refining the model scattering against the simulation-derived scattering pattern, and are found to be significantly different from those correlation lengths derived directly from the MD trajectories. Furthermore, the convergence between the model-derived and MD-derived scattering is poor. The second model, in which the displacement correlations are calculated from the principal components of the MD trajectories, is capable of fully reproducing the MD-derived diffuse scattering if the approximately 50% lowest-frequency modes are included. However, a small number ( approximately 10) of lowest-frequency and largest-amplitude modes dominates the diffuse scattering and thus the correlated protein motions. A detailed analysis of the principal components is performed. In particular, the effective free energy profile associated with each principle mode is analyzed and the eigenfrequency and damping coefficient computed using a model of Brownian dynamics. Those collective modes with effective frequencies below approximately 0.5 THz, including those that determine the diffuse scattering, are overdamped. 相似文献
12.
In this article, we develop an extensive search procedure of the multi‐dimensional folding energy landscape of a protein. Our aim is to identify different classes of structures that have different aggregation propensities and catalytic activity. Following earlier studies by Daggett et al. [Jong, D. D.; Riley, R.: Alonso, D.O.: Dagett, V. J. Mol. Biol. 2002, 319, 229], a series of high temperature all‐atom classical molecular simulation studies has been carried out to derive a multi‐dimensional property space. Dynamical changes in these properties are then monitored by projecting them along a one‐dimensional reaction coordinate, dmean. We have focused on the application of this method to partition a wide array of conformations of wild type human carbonic anhydrase II (HCA II) and its unstable mutant His‐107‐Tyr along dmean by sampling a 35‐dimensional property space. The resultant partitioning not only reveals the distribution of conformations corresponding to stable structures of HCA II and its mutant, but also allows the monitoring of several partially unfolded and less stable conformations of the mutant. We have investigated the population of these conformations at different stages of unfolding and collected separate sets of structures that are widely separated in the property space. The dynamical diversity of these sets are examined in terms of the loading of their respective first principal component. The partially unfolded structures thus collected are qualitatively mapped on to the experimentally postulated light molten globule (MGL) and molten globule (MG) intermediates with distinct aggregation propensities and catalytic activities. Proteins 2016; 84:726–743. © 2016 Wiley Periodicals, Inc. 相似文献
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We found that in proteins the average atomic fluctuation is linearly related to the square of the atomic distance from the center of mass of the protein. Using this simple relation, we can accurately compute the temperature factors of proteins of a wide range of sizes and folds, and the correlation of the fluctuations in proteins. This simple relation provides a direct link between protein dynamics and the static protein's geometrical shape and offers a simple way to compute protein dynamics without either long time trajectory integration or any matrix operations. 相似文献
15.
The 70 kDa heat shock proteins (Hsp70) are a family of molecular chaperones involved in protein folding, aggregate prevention, and protein disaggregation. They consist of the substrate‐binding domain (SBD) that binds client substrates, and the nucleotide‐binding domain (NBD), whose cycles of nucleotide hydrolysis and exchange underpin the activity of the chaperone. To characterize the structure–function relationships that link the binding state of the NBD to its conformational behavior, we analyzed the dynamics of the NBD of the Hsp70 chaperone from Bos taurus (PDB 3C7N:B) by all‐atom canonical molecular dynamics simulations. It was found that essential motions within the NBD fall into three major classes: the mutual class, reflecting tendencies common to all binding states, and the ADP‐ and ATP‐unique classes, which reflect conformational trends that are unique to either the ADP‐ or ATP‐bound states, respectively. “Mutual” class motions generally describe “in‐plane” and/or “out‐of‐plane” (scissor‐like) rotation of the subdomains within the NBD. This result is consistent with experimental nuclear magnetic resonance data on the NBD. The “unique” class motions target specific regions on the NBD, usually surface loops or sites involved in nucleotide binding and are, therefore, expected to be involved in allostery and signal transmission. For all classes, and especially for those of the “unique” type, regions of enhanced mobility can be identified; these are termed “hot spots,” and their locations generally parallel those found by NMR spectroscopy. The presence of magnesium and potassium cations in the nucleotide‐binding pocket was also found to influence the dynamics of the NBD significantly. Proteins 2015; 83:282–299. © 2014 Wiley Periodicals, Inc. 相似文献
16.
A replica exchange molecular dynamics (REMD) simulation of a bicyclic azobenzene peptide in explicit dimethyl sulfoxide solution is presented in order to characterize the conformational structures and energy landscape of a photoswitchable peptide. It is shown that an enhanced-sampling technique such as the REMD method is essential to obtain a converged conformational sampling of the peptide at room temperature. This is because conventional MD simulations of less than approximately 100-ns length are either trapped in local minima (at 295 K) or-if run at high temperature-do not resemble the room-temperature REMD results. Calculating various nuclear Overhauser effects (NOEs) and (3)J-couplings, a good overall agreement between the REMD simulations and the NMR experiments of Renner et al. (Biopolymers 2000;54:501-514) is found. In particular, the REMD study confirms the general picture drawn by Renner et al. that the trans-isomer of the azobenzene peptide exhibits a well-defined structure, while the cis-isomer is a conformational heterogeneous system; that is, the trans-isomer occurs in 2 well-defined conformers, while the cis-isomer represents an energetically frustrated system that leads to an ensemble of conformational structures. Employing a principal component analysis of the REMD data, the free energy landscape of the systems is studied at various temperatures. The implications for the folding and unfolding pathways of the system are discussed. 相似文献
17.
The chromatin modification is regulated by the histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes; abnormal function of these enzymes leads to several malignant diseases. The inhibition of these enzymes using natural ligand molecules is an emerging technique to cure these diseases. The in vitro analysis of natural molecules, venenatine, spinosine, palmatine and taxodione are giving the best inhibition rate against p300 HAT enzyme. However, the detailed understanding of binding and the stability of these molecules with p300 HAT is not yet known. The aim of the present study is focused to determine the binding strength of the molecules from molecular dynamics simulation analysis. The docking analysis confirms that, the venenatine (−6.97 kcal/mol - conformer 8), spinosine (−6.52 kcal/mol conformer −10), palmatine (−5.72 kcal/mol conformer-3) and taxodione (−4.99 kcal/mol conformer-4) molecules form strong hydrogen bonding interactions with the key amino acid residues (Arg1410, Thr1411 and Trp1466) present in the active site of p300. In the molecular dynamics (MD) simulation, the spinosine retain these key interactions with the active site amino acid residues (Arg1410, Thr1411, and Trp1466) than venenatine and are stable throughout the simulation. The RMSD value of spinosine (0.5 to 1.3 Å) and venenatine (0.3 to 1.3 Å) are almost equal during the MD simulation. However, during the MD simulation, the intermolecular interaction between venenatine and the active site amino acid residues (Arg1410, Thr1411, and Trp1466) decreased on comparing with the spinosine-p300 interaction. The binding free energy of the spinosine (−15.30 kcal/mol) is relatively higher than the venenatine (−11.8 kcal/mol); this increment is attributed to the strong hydrogen bonding interactions of spinosine molecule with the active site amino acid residues of p300. 相似文献
18.
Central to the study of a complex dynamical system is knowledge of its phase space behavior. Experimentally, it is rarely possible to record a system's (multidimensional) phase space variables. Rather, the system is observed via one (or few) scalar-valued signal(s) of emission or response. In dynamical systems analysis, the multidimensional phase space of a system can be reconstructed by manipulation of a one-dimensional signal. The trick is in the construction of a (higher-dimensional) space through the use of a time lag (or delay) on the signal time series. The trajectory in this embedding space can then be examined using phase portraits generated in selected subspaces. By contrast, in computer simulation, one has an embarrassment of riches: direct access to the complete multidimensional phase space variables, at arbitrary time resolution and precision. Here, the problem is one of reducing the dimensionality to make analysis tractable. This can be achieved through linear or nonlinear projection of the trajectory into subspaces containing high information content. This study considers trajectories of the small protein crambin from molecular dynamics simulations. The phase space behavior is examined using principal component analysis on the Cartesian coordinate covariance matrix of 138 dimensions. In addition, the phase space is reconstructed from a one dimensional signal, representing the radius of gyration of the structure along the trajectory. Comparison of low-dimensional phase portraits obtained from the two methods shows that the complete phase space distribution is well represented by the reconstruction. The study suggests that it may be possible to develop a deeper connection between the experimental and simulated dynamics of biomolecules via phase space reconstruction using data emerging from recent advances in single-molecule time-resolved biophysical techniques. 相似文献
19.
A comparison is made between a 200-ps molecular dynamics simulation in vacuum and a normal mode analysis on the protein bovine pancreatic trypsin inhibitor (BPTI) in order to elucidate the dual aspects of harmonicity and anharmonicity in the dynamics of proteins. The molecular dynamics trajectory is analyzed using principal component analysis, an effective harmonic analysis suited for comparison with the results from the normal mode analysis. The results suggest that the first principal component shows qualitatively different behavior from higher principal components and is associated with apparent barrier crossing events on an anharmonic conformational energy surface. The higher principal components appear to have probability distributions that are well approximated by Gaussians, indicating harmonicity. Eliminating the contribution from the first principal component reveals a great deal of correspondence between the 2 methods. This correspondence, however, involves a factor of 2, as the variances of the distribution of the higher principal components are, on average, roughly twice those found from the normal mode analysis. A model is proposed to reconcile these results with those from previous analyses. 相似文献
20.
Marlet Martínez-Archundia José Correa-Basurto Sarita Montaño 《Journal of biomolecular structure & dynamics》2013,31(18):4685-4700
AbstractAdenosine receptors (ARs) belong to family A of GPCRs that are involved in many diseases, including cerebral and cardiac ischemic diseases, immune and inflammatory disorders, etc. Thus, they represent important therapeutic targets to treat these conditions. Computational techniques such as molecular dynamics (MD) simulations permit researchers to obtain structural information about these proteins, and principal component analysis (PCA) allows for the identification of collective motions. There are available structures for the active form (3QAK) and the inactive form (3EML) of A2AR which permit us to gain insight about their activation/inactivation mechanism. In this work, we have proposed an inverse strategy using MD simulations where the active form was coupled to the antagonist caffeine and the inactive form was coupled to adenosine agonist. Moreover, we have included four reported thermostabilizing mutations in the inactive form to study A2AR structural differences under different conditions. Some observations stand out from the PCA studies. For instance, the apo structures showed remarkable similarities, and the principal components (PCs) were rearranged in a ligand-dependent manner. Additionally, the active conformation was less stable compared to the inactive one. Some PCs inverted their direction in the presence of a ligand, and comparison of the PCs between 3EML and 3EML_ADN showed that adenosine induced major changes in the structure of A2AR. Rearrangement of PCs precedes and drives conformational changes that occur after ligand binding. Knowledge about these conformational changes provides important insights about the activity of A2AR. 相似文献