Molecular Modeling and Affinity Determination of scFv Antibody: Proper Linker Peptide Enhances Its Activity

One of existing strategies to engineer active antibody is to link VH and VL domains via a linker peptide. How the composition, length, and conformation of the linker affect antibody activity, however, remains poorly understood. In this study, a dual approach that coordinates molecule modeling, biological measurements, and affinity evaluation was developed to quantify the binding activity of a novel stable miniaturized anti-CD20 antibody or singlechain fragment variable (scFv) with a linker peptide. Upon computer-guided homology modeling, distance geometry analysis, and molecular superimposition and optimization, three new linker peptides PT1, PT2, and PT3 with respective 7, 10, and 15 residues were proposed and three engineered antibodies were then constructed by linking the cloned VH and VL domains and fusing to a derivative of human IgG1. The binding stability and activity of scFv-Fc chimera to CD20 antigen was quantified using a micropipette adhesion frequency assay and a Scatchard analysis. Our data indicated that the binding affinity was similar for the chimera with PT2 or PT3 and ~24-fold higher than that for the chimera with PT1, supporting theoretical predictions in molecular modeling. These results further the understanding in the impact of linker peptide on antibody structure and activity.

Structure analysis of CCR5 from human and primates

It is well known that the chemokine receptor CCR5 plays very important roles in HIV-1 virus infection. A three-dimensional molecular model of human CCR5 was generated by SYBYL, a distance geometry-based homologous modeling package, using the corresponding transmembrane domain of bacteriorhodopsin as the template. On the basis of human CCR5 model, we also built 18 3D molecular models of CCR5 in primates from Pongo pygmaeus, Pygathrix nemaeus, Macaca assameniss, Trachy-pithecus phayrei, T. francoisi, M. arotoides, Rhinopithecus roxellance, R, bieti, R. avunculus, Hylobates leucogenys, Pan troglodytes, Gorilla gorilla, Cercopithecus aethiops 1, C. aethiops 2, Papio hamadryas M. mulatta, M. fascicularis and M. nemestrina. Structural analyses and statistics results suggested that the main-chains of the primate CCR5 were similar to that of the human CCR5 and that the fit-RMS deviation values of these primate CCR5 were less than 0.1 Angstrom. Moreover, the structures of these CCR5 proteins, except those of the African green monkey 1 (C.aet1), do not have a remarkable difference. It is proved that the 14th residue is possibly very important in the inhibition infections by M-tropic HIV-1, and it is also demonstrated that the 13th residue of human CCR5 was changed from asparagine into aspartic acid in all these primates. It means that the primate CCR5 no longer depend on CD4 for efficient entry, but human CCR5 may have evolved subsequently due to the use of CD4 as a receptor, allowing the high-affinity chemokine receptor-binding site of HIV to be sequestered from host immune surveillance. (C) 2000 Elsevier Science B.V. All rights reserved.

Three dimensional solution structure of neurotoxin CM-11 from the Ophiophagus hannah

The Ophiophagus hannah (King Cobra) neurotoxin CM-11 is a small protein with 72 amino acid residues, Based on complete assignments of H-1-NMR resonances and determination of secondary structures of CM-11, 349 distance and 27 dihedral angle constraints including 19 phi's and 8 chi's were collected from NOESY and DQF-COSY , and the chemical stereospecific assignment of beta(1)H was partially achieved, Twelve structures with lower energy was obtained via metric matrix distance geometry and refinement with simulated annealing, These structures have a low RMSD of 0.14 nm for backbone atoms and 0.20 nm for heavy atoms, with no distance constraint violation more than 0.05 nm, and no dihedral angle violation more than 3 degrees.

Phylogeny of SARS-CoV based on high-dimensional information geometry

We proposed a novel methodology, which firstly, extracting features from species' complete genome data, using k-tuple, followed by studying the evolutionary relationship between SARS-CoV and other coronavirus species using the method, called "High-dimensional information geometry". We also used the mothod, namely "caculating of Minimum Spanning Tree", to construct the Phyligenetic tree of the coronavirus. From construction of the unrooted phylogenetic tree, we found out that the evolution distance between SARS-CoV and other coronavirus species is comparatively far. The tree accurately rebuilt the three groups of other coronavirus. We also validated the assertion from other literatures that SARS-CoV is similar to the coronavirus species in Group I.

A face detection algorithm based on high dimensional space geometry

In this paper, a face detection algorithm which is based on high dimensional space geometry has been proposed. Then after the simulation experiment of Euclidean Distance and the introduced algorithm, it was theoretically analyzed and discussed that the proposed algorithm has apparently advantage over the Euclidean Distance. Furthermore, in our experiments in color images, the proposed algorithm even gives more surprises.

An algorithm of analysis tools on points distribution in high dimension space: The distance of a point and an infinite sub-space

This paper discusses the algorithm on the distance from a point and an infinite sub-space in high dimensional space With the development of Information Geometry([1]), the analysis tools of points distribution in high dimension space, as a measure of calculability, draw more attention of experts of pattern recognition. By the assistance of these tools, Geometrical properties of sets of samples in high-dimensional structures are studied, under guidance of the established properties and theorems in high-dimensional geometry.

MOLECULAR-GEOMETRY AND CHAIN ENTANGLEMENT - PARAMETERS FOR THE TUBE MODEL

The tube diameter in the reptation model is the distance between a given chain segment and its nearest segment in adjacent chains. This dimension is thus related to the cross-sectional area of polymer chains and the nearest approach among chains, without effects of thermal fluctuation and steric repulsion. Prior calculated tube diameters are much larger, about 5 times, than the actual chain cross-sectional areas. This is ascribed to the local freedom required for mutual rearrangement among neighboring chain segments. This tube diameter concept seems to us to infer a relationship to the corresponding entanglement spacing. Indeed, we report here that the critical molecular weight, M(c), for the onset of entanglements is found to be M(c) = 28 A/([R2]0/M), where A is the chain cross-sectional area and [R2]0 the mean-square end-to-end distance of a freely jointed chain of molecular weight M. The new, computed relationship between the critical number of backbone atoms for entanglement and the chain cross-sectional area of polymers, N(c) = A0,44, is concordant with the cross-sectional area of polymer chains being the parameter controlling the critical entanglement number of backbone atoms of flexible polymers.

Boundary knot method for 2D and 3D Helmholtz and convection-diffusion problems under complicated geometry

The boundary knot method (BKM) of very recent origin is an inherently meshless, integration-free, boundary-type, radial basis function collocation technique for the numerical discretization of general partial differential equation systems. Unlike the method of fundamental solutions, the use of non-singular general solution in the BKM avoids the unnecessary requirement of constructing a controversial artificial boundary outside the physical domain. The purpose of this paper is to extend the BKM to solve 2D Helmholtz and convection-diffusion problems under rather complicated irregular geometry. The method is also first applied to 3D problems. Numerical experiments validate that the BKM can produce highly accurate solutions using a relatively small number of knots. For inhomogeneous cases, some inner knots are found necessary to guarantee accuracy and stability. The stability and convergence of the BKM are numerically illustrated and the completeness issue is also discussed.

A Numerical Study of Indentation Using Indenters of Different Geometry

Finite element simulation of the Berkovich, Vickers, Knoop, and cone indenters was carried out for the indentation of elastic-plastic material. To fix the semiapex angle of the cone, several rules of equivalence were used and examined. Despite the asymmetry and differences in the stress and strain fields, it was established that for the Berkovich and Vickers indenters, the load-displacement relation can closely be simulated by a single cone indenter having a semiapex angle equal to 70.3degrees in accordance with the rule of the volume equivalence. On the other hand, none of the rules is applicable to the Knoop indenter owing to its great asymmetry. The finite element method developed here is also applicable to layered or gradient materials with slight modifications.

Deformation twinning and its effect on crack extension

Deformation twinning near a crack tip is observed in b.c.c. metal Mo based on molecular dynamics simulation at temperature T = 50 K and loading rate (K) over dot(II) = 0.0706 MPa m(1/2)/ps. The defor mation twinning is closely controlled by both the crystal geometry orientation and the stress distribution. The width of the deformation twin band is affected by the distance between the upper and lower crack surfaces. The twin plane and twin direction are (<1(1)over bar>2) and [(1) over bar 11], respectively. The initial crack extension occurs in the deformation twin region near the crack tip. The simulation shows that the extension direction of the crack is changed as the crack propagates over the twinning boundary.

Dependence of collision frequency on distance between two hard-sphere particles estimated by computer simulation

A Monte Carlo simulation is performed to study the dependence of collision frequency on interparticle distance for a system composed of two hard-sphere particles. The simulation quantitatively shows that the collision frequency drops down sharply as the distance between two particles increases. This characteristic provides a useful evidence for the collision-reaction dynamics of aggregation process for the two-particle system described in the other reference.

A geometry model for tortuosity of flow path in porous media

A simple geometry model for tortuosity of flow path in porous media is proposed based on the assumption that some particles in a porous medium are unrestrictedly overlapped and the others are not. The proposed model is expressed as a function of porosity and there is no empirical constant in this model. The model predictions are compared with those from available correlations obtained numerically and experimentally, both of which are in agreement with each other. The present model can also give the tortuosity with a good approximation near the percolation threshold. The validity of the present tortuosity model is thus verified.

Fractal geometry model for effective thermal conductivity of three-phase porous media

An approximate model, a fractal geometry model, for the effective thermal conductivity of three-phase/unsaturated porous media is proposed based on the thermal-electrical analogy technique and on statistical self-similarity of porous media. The proposed thermal conductivity model is expressed as a function of porosity (related to stage n of Sierpinski carpet), ratio of areas, ratio of component thermal conductivities, and saturation. The recursive algorithm for the thermal conductivity by the proposed model is presented and found to be quite simple. The model predictions are compared with the existing measurements. Good agreement is found between the present model predictions and the existing experimental data. This verifies the validity of the proposed model. (C) 2004 American Institute of Physics.

Estimation of Correlation Distance of Soil Properties by Geostatistics

Random field theory has been used to model the spatial average soil properties, whereas the most widely used, geostatistics, on which also based a common basis (covariance function) has been successfully used to model and estimate natural resource since 1960s. Therefore, geostistics should in principle be an efficient way to model soil spatial variability Based on this, the paper presents an alternative approach to estimate the scale of fluctuation or correlation distance of a soil stratum by geostatistics. The procedure includes four steps calculating experimental variogram from measured data, selecting a suited theoretical variogram model, fitting the theoretical one to the experimental variogram, taking the parameters within the theoretical model obtained from optimization into a simple and finite correlation distance 6 relationship to the range a. The paper also gives eight typical expressions between a and b. Finally, a practical example was presented for showing the methodology.