Biomedical subjects

Jianpeng Ma

Publications and source records attributed to Jianpeng Ma.

12 recordsLinked to original sources

PubMed2003

A structural-informatics approach for mining beta-sheets: locating sheets in intermediate-resolution density maps.

Here, we report a new computational method, called sheetminer, for mining beta-sheets in the density maps at intermediate resolutions of 6 to 10A. The method employs a multi-step ad hoc morphological analysis of density maps to identify the unique characteristics of beta-sheets. It was tested on density maps from 12 protein crystal structures that were artificially blurred to intermediate resolutions. There are a total of 35 independent beta-sheets with a wide distribution of morphology. The method successfully located 34 of them and missed only one. The method was also applied to an experimental 9A electron cryomicroscopic structure and an 8A X-ray density map. In both cases, the sheet-searching results were found to agree very well with known high-resolution crystal structures. Collectively, these results demonstrate clearly the robustness of sheetminer in locating the regions belonging to beta-sheets in the intermediate-resolution density maps. Furthermore, sheetminer is completely complementary to all other existing computational methods, including helixhunter and threading algorithms. Their combined usage has the potential to significantly enhance the computational modeling capacity for a much more complete interpretation of structural data at intermediate resolutions, from which extraction of functional information would be more effective. This is particularly important in the field of structural genomics, in which the fast screening approach may not always yield crystals that diffract to atomic resolution. An exciting future application of sheetminer is as a valuable tool for revealing the structures of amyloid fibrils that are rich in beta-motifs.

Algorithms↗

PubMed2003

Conformational flexibility of pyruvate dehydrogenase complexes: a computational analysis by quantized elastic deformational model.

Pyruvate dehydrogenase complex (PDC) is one of the largest multienzyme complexes known and consists of a dodecahedral E2 core to which other components are attached. We report the results of applying a new computational method, quantized elastic deformational model, to simulating the conformational fluctuations of the truncated E2 core, using low-resolution electron cryomicroscopy density maps. The motional features are well reproduced; especially, the symmetric breathing mode revealed in simulation is nearly identical with what was observed experimentally. Structural details of the motions of the trimeric building blocks, which are critical to facilitating the global expansion and contraction of the complex, were revealed. Using the low-resolution maps from electron cryomicroscopy reconstructions, the simulations showed a picture of the motional mechanism of the PDC core, which is an example without precedent of thermally activated global dynamics. Moreover, the current results support an earlier suggestion that, at low resolution and without the use of amino acid sequence and atomic coordinates, it is possible for computer simulations to provide an accurate description of protein dynamics.

Acetyltransferases↗

PubMed2003

Motions and negative cooperativity between p97 domains revealed by cryo-electron microscopy and quantised elastic deformational model.

p97, a Mg-ATPase belonging to the AAA (ATPase associated with various cellular activities) super family of proteins, has been proposed to function in two distinct cellular pathways, namely homotypic membrane fusion and ubiquitin protein degradation by utilizing differing adaptor complexes. We present the cryo-electron microscopy three-dimensional reconstruction of endogenous p97 in an AMP-PNP bound state at 24 A resolution. It reveals clear nucleotide-dependent differences when compared to our previously published "p97-ADP" reconstruction, including a striking rearrangement of N domains and a positional change of the two ATPase domains, D1 and D2, with respect to each other. The docking of the X-ray structure of N-D1 domains in an ADP bound state indicates that an upward repositioning of N domain is necessary to accommodate the cryo-EM map of "p97-AMP-PNP", suggesting a change in the orientation of N domains upon nucleotide hydrolysis. Furthermore, computational analysis of the deformational motions of p97, performed on the cryo-EM density map and the atomic structure of the N-D1 domains independently, shows the existence of a negative cooperativity between the D1 and D2 rings and the flexibility of the N domains. Together these results allow the identification of functionally important features that offer molecular insights into the dynamics of the proposed p97 chaperone function.

Adenosine Triphosphatases↗

PubMed2003

Simulation of F-actin filaments of several microns.

Here we report the results of applying substructure synthesis method to the simulation of F-actin filaments of several microns in length. The elastic deformational modes of long F-actin filaments were generated from the vibrational modes of the 13-subunit repeat of F-actin using a hierarchical synthesis scheme. The computationally synthesized deformational modes, in the very low-frequency regime, are in good agreement with theoretical solutions for long homogeneous elastic rods, which confirmed the usefulness of substructure synthesis method. Other low-frequency modes carry rich local deformational features that are unique to F-actins. All these modes thus provide a theoretical basis set for a description of spontaneously occurring thermal deformations, such as undulations, of the filaments. The results demonstrate that substructure synthesis method, as a method for computational modal analysis, is capable of scaling up the microscopic dynamic information, obtained from atomistic simulations, to a wide range of macroscopic length scale. Moreover, the combination of substructure synthesis method and hierarchical synthesis scheme provides an effective way in dealing with complex systems of periodic repeats that are abundant in cells.

Actin Cytoskeleton↗

PubMed2002

Substructure synthesis method for simulating large molecular complexes.

This paper reports a computational method for describing the conformational flexibility of very large biomolecular complexes using a reduced number of degrees of freedom. It is called the substructure synthesis method, and the basic concept is to treat the motions of a given structure as a collection of those of an assemblage of substructures. The choice of substructures is arbitrary and sometimes quite natural, such as domains, subunits, or even large segments of biomolecular complexes. To start, a group of low-frequency substructure modes is determined, for instance by normal mode analysis, to represent the motions of the substructure. Next, a desired number of substructures are joined together by a set of constraints to enforce geometric compatibility at the interface of adjacent substructures, and the modes for the assembled structure can then be synthesized from the substructure modes by applying the Rayleigh-Ritz principle. Such a procedure is computationally much more desirable than solving the full eigenvalue problem for the whole assembled structure. Furthermore, to show the applicability to biomolecular complexes, the method is used to study F-actin, a large filamentous molecular complex involved in many cellular functions. The results demonstrate that the method is capable of studying the motions of very large molecular complexes that are otherwise completely beyond the reach of any conventional methods.

Actins↗

PubMed2002

Band gap fluorescence from individual single-walled carbon nanotubes.

Fluorescence has been observed directly across the band gap of semiconducting carbon nanotubes. We obtained individual nanotubes, each encased in a cylindrical micelle, by ultrasonically agitating an aqueous dispersion of raw single-walled carbon nanotubes in sodium dodecyl sulfate and then centrifuging to remove tube bundles, ropes, and residual catalyst. Aggregation of nanotubes into bundles otherwise quenches the fluorescence through interactions with metallic tubes and substantially broadens the absorption spectra. At pH less than 5, the absorption and emission spectra of individual nanotubes show evidence of band gap-selective protonation of the side walls of the tube. This protonation is readily reversed by treatment with base or ultraviolet light.

Journal Article↗

PubMed2002

How to describe protein motion without amino acid sequence and atomic coordinates.

This paper reports a computational method, the quantized elastic deformational model, that can reliably describe the conformational flexibility of a protein in the absence of the amino acid sequence and atomic coordinates. The essence of this method lies in the fact that, in modeling the functionally important conformational changes such as domain movements, it is possible to abandon the traditional concepts of protein structure (bonds, angles, dihedrals, etc.) and treat the protein as an elastic object. The shape and mass distribution of the object are described by the electron density maps, at various resolutions, from methods such as x-ray diffraction or cryo-electron microscopy. The amplitudes and directionality of the elastic deformational modes of a protein, whose patterns match the biologically relevant conformational changes, can then be derived solely based on the electron density map. The method yields an accurate description of protein dynamics over a wide range of resolutions even as low as 15-20 A at which there is nearly no visually distinguishable internal structures. Therefore, this method dramatically enhances the capability of studying protein motions in structural biology. It is also expected to have ample applications in related fields such as bioinformatics, structural genomics, and proteomics, in which one's ability to extract functional information from the not-so-well-defined structural models is vitally important.

Amino Acid Sequence↗

PubMed2002

Domain movements in human fatty acid synthase by quantized elastic deformational model.

This paper reports the results of applying a computational method called the quantized elastic deformational model, to the determination of conformational flexibility of the supermolecular complex of human fatty acid synthase. The essence of this method is the ability to model large-scale conformational changes such as domain movements by treating the protein as an elastic object without the knowledge of protein primary sequence and atomic coordinates. The calculation was based on the electron density maps of the synthase at 19 A. The results suggest that the synthase is a very flexible molecule. Two types of flexible hinges in the structure were identified. One is an intersubunit hinge formed by the intersubunit connection and the other is an intrasubunit hinge located between domains I and II. Despite the fact that the dimeric synthase has a chemically symmetric structure, large domain movements around the hinge region occur in various directions and allow the molecule to adopt a wide range of conformations. These domain movements are likely to be important in facilitating and regulating the entire palmitate synthesis by coordinating the communication between components of the molecule, for instance, adjusting the distance between various active sites inside the catalytic reaction center. Finally, the ability to describe protein motions of a supermolecular complex, without the information of protein sequence and atomic coordinates, is a major advance in computational modeling of protein dynamics. The method provides an unprecedented ability to model protein motions at such a low resolution of structure.

Elasticity↗

PubMed2002

Conformational pathways in the gating of Escherichia coli mechanosensitive channel.

The pathway of the gating conformational transition of Escherichia coli mechanosensitive channel was simulated, using the recently modeled open and closed structures, by targeted molecular dynamics method. The transition can be roughly viewed as a four-stage process. The initial motion under a lower tension load is predominantly elastic deformation. The opening of the inner hydrophobic pore on a higher tension load takes place after the major expansion of the outer channel dimension. The hypothetical N-terminal S1 helical bundle has been confirmed to form the hydrophobic gate, together with the M1 helices. The sequential breaking of the tandem hydrophobic constrictions on the M1 and S1 helices makes the two parts of the gate strictly coupled, acting as a single gate. The simulation also revealed that there is no significant energetic coupling between the inner S1 bundle and the outer M2 transmembrane helices. The molten-globular-like structural features of the S1 bundle in its intermediate open states may account for the observed multiple subconductance states. Moreover, the intermediate open states of mechanosensitive channels are not symmetric, i.e., the opening does not follow iris-like motion, which sharply contrasts to the potassium channel KcsA.

Cytoplasm↗

PubMed2002

Molecular dynamics analysis of a buckyball-antibody complex.

This is a multinanosecond molecular dynamics study of a bio-nano complex formed by a carbon nanoparticle, a buckyball C(60), and a biological molecule, an antibody, with high binding affinity and specificity. In the simulation, the ball is completely desolvated by the binding site of the antibody by means of a nearly perfect shape complementarity and extensive side-chain interactions, with the exception that about 17% of the surface is persistently exposed to solvent and could be used for functional derivatization. The interactions are predominantly hydrophobic, but significant polar interactions occur as well. There exists a rich body of various pi-stacking interactions. Aromatic side chains are involved in both double and triple stackings with the ball. Some ionic side chains, such as the guanidinium group of arginine, also form pi-stackings with the ball. The results suggest that pi-stackings are very efficient and common modes of biological recognition of pi-electron-rich carbon nanoparticles. Most importantly, the results demonstrate that, in general, an ordinary protein binding site, such as that of an antibody, can readily bind to a carbon nanoparticle with high affinity and specificity through recognition modes that are common in protein-ligand recognition.

Antibodies↗

PubMed2002

Intrinsic flexibility and gating mechanism of the potassium channel KcsA.

The gating mechanism of the potassium channel KcsA was studied by normal mode analysis. The results provided an atomic description of the locations of the pivot points and the motional features of key structural elements in the gating process. Two pivot points were found in the motions of the inner TM2 helical bundle that directly modulate the size of the central channel pore. One point is an intrasubunit hinge point that sharply divides the structural flexibility between the more rigid selectivity filter and the more mobile peripheral transmembrane helices. Such a division is vital for KcsA because it permits the large-scale motions of transmembrane helices required for the gating and, in the meantime, maintains the rigidity of the filter region essential for the selectivity. The other pivot point is an intersubunit one at which all four TM2 helices are bundled together. During the gating process, each TM2 helix undergoes a lever-like swinging motion pivoting on the intrasubunit hinge, and the entire TM2 bundle undergoes a concerted rotational motion around the central channel axis constrained around the intersubunit bundle point. This series of motions leads to a dramatic enlargement of the intracellular gate without loosening up the structural integrity.

Bacterial Proteins↗

PubMed2002

A dynamic analysis of the rotation mechanism for conformational change in F(1)-ATPase.

Molecular dynamics trajectories for the bovine mitochondrial F(1)-ATPase are used to demonstrate the motions and interactions that take place during the elementary (120 degrees rotation) step of the gamma subunit. The results show how rotation of the gamma subunit induces the observed structural changes in the catalytic beta subunits. Both steric and electrostatic interactions contribute. An "ionic track" of Arg and Lys residues on the protruding portion of the gamma subunit plays a role in guiding the motions of the beta subunits. Experimental data for mutants of the DELSEED motif and the hinge region are interpreted on the basis of the molecular dynamics results. The trajectory provides a unified dynamic description of the coupled subunit motions involved in the 120 degrees rotation cycles of F(1)-ATPase.

Crystallography, X-Ray↗