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Elastin is a cross-linked protein in the extracellular matrix that provides elasticity for many tissues. Its soluble precursor (tropoelastin) has two major types of alternating domains: (1) hydrophilic cross-linked domains rich in Lys and Ala and (2) hydrophobic domains (responsible for elasticity) rich in Val, Pro, and Gly, which often occur in repeats of VPGVG or VGGVG. Since native elastin is large and insoluble, many studies have focused on elastin-based peptides in an effort to elucidate its structure-function relationship. This review focuses on the molecular basis of elastin's conformational properties and associated elasticity. From both experimental and simulation approaches, elastin can be described as a two-phase model consisting of dynamic hydrophobic domains in water. The hydrophobic domain of elastin is best described as a compact amorphous structure with distorted beta-strands, fluctuating turns, buried hydrophobic residues, and main-chain polar atoms that from hydrogen bonds with water. Water plays a critical role in determining elastin's conformational behavior, making elastin extremely dynamic in its relaxed state and providing an important source of elasticity.
Rigidity of initial fixation is a key factor contributing to the longevity of cemented and cementless femoral components in total hip arthroplasty. The objective of this study was to measure the initial stability of primary cemented and cementless femoral components under load when 15 pairs of cadaveric femurs were prepared by outward compaction of femoral cancellous bone in situ or by conventional extraction broaching. Three-dimensional micromotion was measured at proximal and distal locations on the femoral components using a device with spherical targets and linear variable differential transformers. External loads simulating the stance phases of level walking and stair ascent were applied to the femoral components by a materials test machine. Bone preparation method significantly affected each of the translation and rotation components of micromotion with cemented and cementless fixation. Micromotion with broaching was consistently greater than with compaction. Compared with compaction, the magnitude of the micromotion translation vector for broaching was an average of 3.9 (standard deviation, 3.1) times greater with cemented fixation, and an average of 2.3 (standard deviation, 1.4) times greater with cementless fixation. The results of this study showed the effectiveness of compaction of femoral cancellous bone in improving the initial stability of cemented and cementless femoral components in primary total hip arthroplasty.
Compaction of a nascent polypeptide chain inside the ribosomal exit tunnel, before it leaves the ribosome, has been proposed to accelerate the folding of newly synthesized proteins following their release from the ribosome. Thus, we used Kinetic Monte Carlo simulations of a minimalist on-lattice model to explore the effect that polypeptide translocation through a variety of channels has on protein folding kinetics. Our results demonstrate that tunnel confinement promotes faster folding of a well-designed protein relative to its folding in free space by displacing the unfolded state towards more compact structures that are closer to the transition state. Since the tunnel only forbids rarely visited, extended configurations, it has little effect on a "poorly designed" protein whose unfolded state is largely composed of low-energy, compact, misfolded configurations. The beneficial effect of the tunnel depends on its width; for example, a too-narrow tunnel enforces unfolded states with limited or no access to the transition state, while a too-wide tunnel has no effect on the unfolded state entropy. We speculate that such effects are likely to play an important role in the folding of some proteins or protein domains in the cellular environment and might dictate whether a protein folds co-translationally or post-translationally.
Aldose reductase (AR) is a key enzyme in the polyol pathway and plays a major role in the progression of secondary complications of diabetes. Despite extensive efforts to develop natural and synthetic aldose reductase inhibitors (ARIs), most candidates have shown limited clinical efficacy, highlighting the need for more potent and selective inhibitors. In this study, we have systematically evaluated the inhibitory potential of vitamin K family members (vitamin K1, vitamin K2, and vitamin K3) using molecular docking, protein-ligand interaction analysis, molecular dynamics simulations, and enzyme kinetics. Docking analysis predicted that vitamin K2 has the highest binding affinity for AR. Subsequent molecular dynamics simulations revealed that both vitamin K1 and vitamin K2 formed stable complexes with the protein, exhibiting comparable RMSD (∼0.5 Å difference), similar RMSF profiles, and reduced radius of gyration, indicating compact and stable binding. Interaction analysis demonstrated that ligand binding is predominantly driven by hydrophobic interactions, with vitamin K2 forming a higher number of hydrophobic contacts, while vitamin K1 exhibited slightly more hydrogen bonding. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) results further supports stronger binding of vitamin K2 (-56 kcal/mol) compared to vitaminK1 (-51 kcal/mol). Consistent with these findings, enzyme kinetics showed a slightly lower Ki value for vitamin K2 than vitamin K1. In contrast, vitamin K3 failed to maintain stable binding and moved out of the active site during simulation. Overall, the study highlights that hydrophobic interaction-driven stabilization plays a key role in ligand binding, and identifies vitamin K1 and vitamin K2 as promising inhibitors against AR, with vitamin K2 exhibiting more favourable hydrophobic interactions and binding stability.
The particle volume of a protein which represents the expansion of the molecular chain is a useful probe to measure its conformation change in solution. To study the details of the conformation transition, we will report a novel device to trace the particle-volume change against increasing denaturant concentration. According to the denaturant gradient in the eluant of high-performance gel-permeation chromatography, information concerning the elution volume of proteins in the course of denaturation can be successively accessed. When a protein is injected into a denaturant solution, its effective molecular volume increases by the unfolding of a native compact structure, and the elution peak goes forward to separate from that of the native protein. Typical elution patterns were computer-simulated in an extended algorithm of the plate theory. The kinetic feature of denaturation and the effect of the denaturant gradient are discussed. The denaturation schemes of lysozyme, cytochrome c, and phosphoglycerate kinase were studied.
Reconstructing a protein in three dimensions from its backbone torsion angles is an ongoing challenge because minor inaccuracies in these angles produce major errors in the structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm, the longer the arm, the larger the displacement. Even accurate knowledge of the backbone torsions and Psi is insufficient, owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, also lead to major errors in the structure. Against this background, we conducted a computational experiment to assess whether protein conformation can be determined from highly approximate backbone torsion angles, the kind of information that is now obtained readily from NMR. Specifically, backbone torsion angles were taken from proteins of known structure and mapped into 60 degrees x 60 degrees grid squares, called mesostates. Side-chain atoms beyond the beta -carbon were discarded. A mesostate representation of the protein backbone was then used to extract likely candidates from a fragment library of mesostate pentamers, followed by Monte Carlo-based fragment-assembly simulations to identify stable conformations compatible with the given mesostate sequence. Only three simple energy terms were used to gauge stability: molecular compaction, soft-sphere repulsion, and hydrogen bonding. For the six representative proteins described here, stable conformers can be partitioned into a remarkably small number of topologically distinct clusters. Among these, the native topology is found with high frequency and can be identified as the cluster with the most favorable energy.
In this paper we carry out computer simulation studies of some of the factors responsible for protein tertiary structure. We show that it is possible to obtain (fold) a compact globular conformation from a sequence of amino acids consisting of only glycines and alanines. Our results indicate that glycines play a central role in stabilizing globular structures by facilitating the formation of turns and by destabilizing helical structures. Using this simple two-amino-acid representation, which serves as a control experiment, we are able to obtain a conformation that resembles the native structure of pancreatic trypsin inhibitor, as closely as any obtained previously in folding studies. However, careful examination reveals that the true chain topology has not been reproduced here or in previous studies. We suggest that the discrepancies between calculated and observed structures are more significant than the similarities. The implications of these results for the validity of models for protein folding, the use of pancreatic trypsin inhibitor in folding studies, and the possible role of glycine in the evolution of protein structure are discussed.
In this paper, adaptive neural network (NN) control is investigated for a class of discrete-time multi-input-multi-output (MIMO) nonlinear systems with triangular form inputs. Each subsystem of the MIMO system is in strict feedback form. First, through two phases of coordinate transformation, the MIMO system is transformed into input-output representation with the triangular form input structure unchanged. By using high-order neural networks (HONNs) as the emulators of the desired controls, effective output feedback adaptive control is developed using backstepping. The closed-loop system is proved to be semiglobally uniformly ultimate bounded (SGUUB) by using Lyapunov method. The output tracking errors are guaranteed to converge into a compact set whose size is adjustable, and all the other signals in the closed-loop system are proved to be bounded. Simulation results show the effectiveness of the proposed control scheme.
The lobula giant movement detector (LGMD) is a visual interneuron of Orthopteran insects involved in collision avoidance and escape behavior. The LGMD possesses a large dendritic field thought to receive excitatory, retinotopic projections from the entire compound eye. We investigated whether the LGMD's receptive field for local motion stimuli can be explained by its electrotonic structure and the eye's anisotropic sampling of visual space. Five locust (Schistocerca americana) LGMD neurons were stained and reconstructed. We show that the excitatory dendritic field and eye can be fitted by ellipsoids having similar geometries. A passive compartmental model fit to electrophysiological data was used to demonstrate that the LGMD is not electrotonically compact. We derived a spike rate to membrane potential transform using intracellular recordings under visual stimulation, allowing direct comparison between experimental and simulated receptive field properties. By assuming a retinotopic mapping giving equal weight to each ommatidium and equally spaced synapses, the model reproduced the experimental data along the eye equator, though it failed to reproduce the receptive field along the ventral-dorsal axis. Our results illustrate how interactions between the distribution of synaptic inputs and the electrotonic properties of neurons contribute to shaping their receptive fields.
A conformation analysis of tetrapeptide in DMSO was carried out by the Monte Carlo simulation including the solvent effects in the energy function. The lowest energy conformations in the zwitterionic and cationic states are a similar compact form, in which the two aromatic rings are close to each other. The distance distributions between the specified atoms in the molecule show that most conformations in the local energy minima are similar to this folded conformation, although there is another type of conformation of interest, which has an extended form with the two separate aromatic rings. Such results are consistent with the NMR and CD experiments, and suggest that the compact form of tetragastrin is essential as a biological active conformation. The folded structure is stabilized by the solute-solvent interaction. In particular, the nonbonding interactions between the solute and solvent molecules cause a folding effect on the molecular conformation in total. This study is a first case taking account of the solvent effect into the conformation analysis of tetragastrin.
1. Experimental measures of input resistance, RN, and responses to brief hyperpolarizing current pulses were obtained in identified gamma-motoneurons in pentobarbital-anesthetized cats using conventional sharp micropipettes. The same cells were subsequently injected with horseradish peroxidase and completely reconstructed. In two cells, the electrophysiological and morphological data were of sufficient quality to permit estimation of specific membrane resistance, Rm, using biologically plausible ranges of specific cytoplasmic resistance, Ri, and membrane capacitance, Cm. 2. A combination of steady-state and dynamic computer models were employed to reconcile cell morphology with RN and the trajectories of the voltage decay following brief current pulses delivered to the soma. Simulated transient responses matched the tails of the observed transient when generated with the same current injections used experimentally. With Cm < or = 1.0 microF cm-2, the most satisfactory fits were obtained when the values of Rm assigned to the soma, Rms, were much smaller than the spatially uniform value assigned to the dendrites, Rmd and Ri = 60-70 omega cm. With Cm = 1.0 microF cm-2, Rms ranged from 260 to 427 omega cm2, whereas Rmd was approximately 33 K omega cm2. With Cm = 0.8 microF cm-2, Rms ranged from 235 to 357 omega cm2 and Rmd was between 62 and 68 K omega cm2. When Rm was constrained to be spatially uniform (i.e., Rm = Rms), implausibly high values of Cm (2.5-5.0 microF cm-2; Ri = 70 omega cm) were required to match the observed tail time constant, tau o,peel, but the simulated transients did not otherwise match those obtained experimentally. 3. With best fit values of Rms and Rmd, both gamma-motoneurons were electronically relatively compact (80% of total membrane area within 0.85 length constants from the soma). However, the calculated average steady-state inward attenuation factor (AFin) for voltages generated at any point within the dendrites increased rapidly with distance from the soma, reaching levels of < or = 90 and < or = 45 for the proximal 80% of membrane area for the respective motoneurons in the presence of a somatic shunt (Rms << Rmd). If we assume that the somatic shunt is an artifact of sharp micropipette penetration (i.e., that Rms = Rmd for uninjured cells), then AFin decreased to < or = 20 and < or = 15, respectively, for the proximal 80% of cell membrane.(ABSTRACT TRUNCATED AT 400 WORDS)
Two different spin labels, N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide (IPSL) and (1-oxyl-2,2,5,5-tetramethylpyrroline-3-methyl) methanethiosulfonate (MTSSL), and two different fluorescent labels 5-((((2-iodoacetyl)amino)-ethyl)amino)naphtalene-1-sulfonic acid (IAEDANS) and 6-bromoacetyl-2-dimetylaminonaphtalene (BADAN), were attached to the introduced C79 in human carbonic anhydrase (HCA II) to probe local structural changes upon unfolding and aggregation. HCA II unfolds in a multi-step manner with an intermediate state populated between the native and unfolded states. The spin label IPSL and the fluorescent label IAEDANS reported on a substantial change in mobility and polarity at both unfolding transitions at a distance of 7.4-11.2 A from the backbone of position 79. The shorter and less flexible labels BADAN and MTSSL revealed less pronounced spectroscopic changes in the native-to-intermediate transition, 6.6-9.0 A from the backbone. At intermediate guanidine (Gu)-HCl concentrations the occurrence of soluble but irreversibly aggregated oligomeric protein was identified from refolding experiments. At approximately 1 M Gu-HCl the aggregation was found to be essentially complete. The size and structure of the aggregates could be varied by changing the protein concentration. EPR measurements and line-shape simulations together with fluorescence lifetime and anisotropy measurements provided a picture of the self-assembled protein as a disordered protein structure with a representation of both compact as well as dynamic and polar environments at the site of the molecular labels. This suggests that a partially folded intermediate of HCA II self-assembles by both local unfolding and intermolecular docking of the intermediates vicinal to position 79. The aggregates were determined to be 40-90 A in diameter depending on the experimental conditions and spectroscopic technique used.
We use long multiple trajectories generated by molecular dynamics simulations to probe the stability of oligomers of Abeta(16-22) (KLVFFAE) peptides in aqueous urea solution. High concentration of urea promotes the formation of beta-strand structures in Abeta(16-22) monomers, whereas in water they adopt largely compact random coil structures. The tripeptide system, which forms stable antiparallel beta-sheet structure in water, is destabilized in urea solution. The enhancement of beta-strand content in the monomers and the disruption of oligomeric structure occur largely by direct interaction of urea with the peptide backbone. Our simulations suggest that the oligomer unbinding dynamics is determined by two opposing effects, namely, by the increased propensity of monomers to form beta-strands and the rapid disruption of the oligomers. The qualitative conclusions are affirmed by using two urea models. Because the proposed destabilization mechanism depends largely on hydrogen bond formation between urea and the peptide backbone, we predict that high urea concentration will destabilize oligomers of other amyloidogenic peptides as well.
A self-assembled, cylindrical capsule was used to bind N-alpha-protected amino acid esters. The reversible encapsulation was studied using NMR spectroscopy in deuterated mesitylene solution and by computer-aided molecular modeling. BOC-L-alanine alkyl esters and BOC-beta-alanine alkyl esters were tested as guests, and the relative binding affinities were established by direct competition experiments. A good correlation was found between the experimental and calculated relative binding affinities in these two series. Guests that were slightly longer than the internal dimensions of the cavity were accommodated by adopting compacted conformations.
The SAR study on a phage library-derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain indicates that the configuration of the cyclization linkage is crucial for assuming the active binding conformation. When the thioether linkage was oxidized to the two chiral sulfoxides, the R-configured sulfoxide-cyclized peptide displayed 10-30 times more potency than the corresponding S-configured one in binding affinity to the Grb2-SH2 domain. In this paper, the solution structures of such a pair of sulfoxide-bridged cyclic peptide diastereoisomers, i.e., cyclo[CH(2)CO-Gla(1)-L-Y-E-N-V-G-NPG-Y-(R/S)C(O)(10)]-amide, were determined by NMR and molecular dynamics simulation. Results indicate that the consensus sequence of Y(3)-E(4)-N(5)-V(6) in both diastereoisomers adopt a beta-turn conformation; however, the R-configured peptide forms an extended structure with a circular backbone conformation, while the S-configured isomer forms a compact structure with key residues buried inside the molecule. The average root-mean-square deviations were found to be 0.756 and 0.804 A, respectively. It is apparent that the chiral S-->O group played a key role in the solution structures of the sulfoxide-bridged cyclic peptides. The R-sulfoxide group forms an intramolecular hydrogen bond with the C-terminal amide, conferring a more rigid conformation with all residues protruding outside except for Leu2, in which the Gla1 and Tyr3 share an overlapping function as previous SAR studies proposed. Additionally, the extended structure endows a more hydrophilic binding surface of the R-configured peptide to facilitate its capture by its targeted protein. In comparison, the S-configured sulfoxide was embedded inside the ligand peptide leading to a compact structure, in which the essential residues of Gla1, Tyr3, and Asn5 form multiple intramolecular hydrogen bonds resulting in an unfavorable conformational change and a substantial loss of the interaction with the protein. The solution structures disclosed by our NMR and molecular dynamics simulation studies provide a molecular basis for understanding how the chirality of the cyclization linkage remarkably discriminates in terms of the binding affinity, thus advancing the rational design of potent non-phosphorylated inhibitors of Grb2-SH2 domain as antitumor agents.
The release properties of phenylpropanolamine hydrochloride (PPA) from ethylcellulose (EC) matrix granules prepared by an extrusion granulation method were examined. The release process could be divided into two parts; the first and second stages were analyzed by applying square-root time law and cube-root law equations, respectively. The validity of the treatments was confirmed by the fitness of a simulation curve with the measured curve. In the first stage, PPA was released from the gel layer of swollen EC in the matrix granules. In the second stage, the drug existing below the gel layer dissolved and was released through the gel layer. The effect of the binder solution on the release from EC matrix granules was also examined. The binder solutions were prepared from various EC and ethanol (EtOH) concentrations. The media changed from a good solvent to a poor solvent with decreasing EtOH concentration. The matrix structure changed from loose to compact with increasing EC concentration. The preferable EtOH concentration region was observed when the release process was easily predictable. The time and release ratio at the connection point of the simulation curves were also examined to determine the validity of the analysis.
In this study the investigations made on about 50 trunk tissue densities are described. They were performed on ten cadavers of both sexes within 24 h of the moment of death. They were 20-40 yr old. The weight of each tissue was measured on a laboratory scale and the volume by placing the tissue in a pycnometer filled with water. The density of 2/3 solid trunk tissues ranged from 1.11 to 1.20 g cm-3. The lowest mean data was obtained for a lung tissue (0.563 g cm-3). The highest density datum known from the literature was that for a compact bone: 1.892 g cm-3. The application of obtained data can be for building dummies (e.g. in experiments of car-crash simulations), as well as in the calculation of inertia values using computerized tomography images.