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At least 19 recordsLinked to original sources
PubMed1992

The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships.

Thrombin is a multifunctional serine proteinase that plays a key role in coagulation while exhibiting several other key cellular bioregulatory functions. The X-ray crystal structure of human alpha-thrombin was determined in its complex with the specific thrombin inhibitor D-Phe-Pro-Arg chloromethylketone (PPACK) using Patterson search methods and a search model derived from trypsinlike proteinases of known spatial structure (Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R., & Hofsteenge, J., 1989, EMBO J. 8, 3467-3475). The crystallographic refinement of the PPACK-thrombin model has now been completed at an R value of 0.156 (8 to 1.92 A); in particular, the amino- and the carboxy-termini of the thrombin A-chain are now defined and all side-chain atoms localized; only proline 37 was found to be in a cis-peptidyl conformation. The thrombin B-chain exhibits the characteristic polypeptide fold of trypsinlike serine proteinases; 195 residues occupy topologically equivalent positions with residues in bovine trypsin and 190 with those in bovine chymotrypsin with a root-mean-square (r.m.s.) deviation of 0.8 A for their alpha-carbon atoms. Most of the inserted residues constitute novel surface loops. A chymotrypsinogen numbering is suggested for thrombin based on the topological equivalences. The thrombin A-chain is arranged in a boomeranglike shape against the B-chain globule opposite to the active site; it resembles somewhat the propeptide of chymotrypsin(ogen) and is similarly not involved in substrate and inhibitor binding. Thrombin possesses an exceptionally large proportion of charged residues. The negatively and positively charged residues are not distributed uniformly over the whole molecule, but are clustered to form a sandwichlike electrostatic potential; in particular, two extended patches of mainly positively charged residues occur close to the carboxy-terminal B-chain helix (forming the presumed heparin-binding site) and on the surface of loop segment 70-80 (the fibrin[ogen] secondary binding exosite), respectively; the negatively charged residues are more clustered in the ringlike region between both poles, particularly around the active site. Several of the charged residues are involved in salt bridges; most are on the surface, but 10 charged protein groups form completely buried salt bridges and clusters. These electrostatic interactions play a particularly important role in the intrachain stabilization of the A-chain, in the coherence between the A- and the B-chain, and in the surface structure of the fibrin(ogen) secondary binding exosite (loop segment 67-80).(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Chloromethyl Ketones↗
PubMed1978

[Rule of antibody structure: the primary structure of a human monoclonal IgA1-immunoglobulin (myeloma protein Tro), V. The arrangement of the tryptic peptides and a discussion of the complete primary structure of the H-chain (author's transl)].

This communication deals with the sequence work done with tryptic and chymotryptic peptides and some cyanogen bromide splitting products. With these peptides, and if necessary with their splitting peptides, the whole primary structure of the alpha1-H-chain of myeloma protein Tro is established. The position of the amides is determined by electrophoresis and digestion with aminopeptidase M. The alpha1-chain Tro comprises 475 amino acid residues. Because of its specific exchanges and deletions the variable part of alpha1-chain Tro belongs to subgroup III of variable parts of H-chains. The switch from the variable to the constant part occurs at position 119/120 and is analogous to other chains which have been sequenced up to now. The large number of cysteine residues in the alpha-chain which may influence the tertiary structure, especially in the hinge and the subsequent CH2-region, is noteworthy. Furthermore, myeloma protein Tro is compared with the other alpha1-chain Bur[5] sequenced in the meantime, and protein But[6], which is an IgA2 molecule of the allotype A2m(2).

Amino Acid Sequence↗
PubMed1976

[The rule of antibody structure. The primary structure of a monoclonal IgG1 immunoglobulin (myeloma protein Nie). III. The chymotryptic peptides of the H-chain, alignment of the tryptic peptides and discussion of the complete structure].

In this final paper the complete primary structure of the H-chain of immunoglobulin Nie (IgG1, Gm1+, 17+) is established by overlapping tryptic fragments with chymotryptic peptides. The preceding papers dealt with the purification of the protein, the characterization of the light and heavy chains, the purification and characterization of the cyanogen bromide cleavage products, the location of the disulfide bonds, the isolation of the tryptic peptides and their sequence determination. The gamma1-chain Nie comprises 448 amino acid residues. When the protein is compared with other H-chains, the switch from the variable to the constant part occurs at position 119/120. Based on the amino acid sequence of the variable part, protein Nie belongs to subgroup III of the H-chains. It was the first protein of this subgroup to be sequenced. In the meantime several other proteins are known which have been assigned to the same subgroup on the basis of linked amino acid exchanges in comparison to members of other subgroups. This confirms the evolutionary origin of antibody variability and hence the genetically fixed antibody specific. Furthermore protein Nie is the first completely determined chain with the genetic factors Gm1+, 17+. These factors are inherited codominantly and are localized on the constant part of the gamma1-chain. By comparison with protein Eu, which is Gml-, 4+ and therefore an allele of Nie, these serologically defined factors are correlated with Eu. Besides the amino acid exchanges caused by the Gm-factors we elucidated a series of differences to the constant part of the protein Eu. These differences include 6 amide postions and the sequence from residues 387 to 391. Using the structure of IgG1 Nie as an example some rules for the evolution of immunoglobulin sequences have been described. In particular the "elongation-rule" and the "Disulfide-rule" are discussed. While chain-elongation of the H-chains can simply be explained by repeated gene duplications of a basic unit containing ca 110 amino acids, the location of disulfide bonds is determined partly by gene duplication, which implies multiplication of evolutionary "old" cystein residues and partly by the relatively recent acquisition of "new" cystein in appropriate sites. Most evident is the origin of the "hindge-region" by partial gene duplication on the C-terminal residues of the first homology region.

Amino Acid Sequence↗
PubMed1992

The solution structure of eglin c based on measurements of many NOEs and coupling constants and its comparison with X-ray structures.

A high-precision solution structure of the elastase inhibitor eglin c was determined by NMR and distance geometry calculations. A large set of 947 nuclear Overhauser (NOE) distance constraints was identified, 417 of which were quantified from two-dimensional NOE spectra at short mixing times. In addition, a large number of homonuclear 1H-1H and heteronuclear 1H-15N vicinal coupling constants were used, and constraints on 42 chi 1 and 38 phi angles were obtained. Structure calculations were carried out using the distance geometry program DG-II. These calculations had a high convergence rate, in that 66 out of 75 calculations converged with maximum residual NOE violations ranging from 0.17 A to 0.47 A. The spread of the structures was characterized with average root mean square deviations ( ) between the structures and a mean structure. To calculate the unbiased toward any single structure, a new procedure was used for structure alignment. A canonical structure was calculated from the mean distances, and all structures were aligned relative to that. Furthermore, an angular order parameter S was defined and used to characterize the spread of structures in torsion angle space. To obtain an accurate estimate of the precision of the structure, the number of calculations was increased until the and the angular order parameters stabilized. This was achieved after approximately 40 calculations. The structure consists of a well-defined core whose backbone deviates from the canonical structure ca. 0.4 A, a disordered N-terminal heptapeptide whose backbone deviates by 0.8-12 A, and a proteinase-binding loop whose backbone deviates up to 3.0 A. Analysis of the angular order parameters and inspection of the structures indicates that a hinge-bending motion of the binding loop may occur in solution. Secondary structures were analyzed by comparison of dihedral angle patterns. The high precision of the structure allows one to identify subtle differences with four crystal structures of eglin c determined in complexes with proteinases.

Amino Acid Sequence↗
PubMed1992

Nuclear magnetic resonance solution structure of hirudin(1-51) and comparison with corresponding three-dimensional structures determined using the complete 65-residue hirudin polypeptide chain.

The three-dimensional structure of the N-terminal 51-residue domain of recombinant hirudin in aqueous solution was determined by 1H nuclear magnetic resonance (NMR) spectroscopy, and the resulting high-quality solution structure was compared with corresponding structures obtained from studies with the intact, 65-residue polypeptide chain of hirudin. On the basis of 580 distance constraints derived from nuclear Overhauser effects and 109 dihedral angle constraints, a group of 20 conformers representing the solution structure of hirudin(1-51) was computed with the program DIANA and energy-minimized with a modified version of the program AMBER. Residues 3 to 30 and 37 to 48 form a well-defined molecular core with two antiparallel beta-sheets composed of residues 14 to 16 and 20 to 22, and 27 to 31 and 36 to 40, and three reverse turns at residues 8 to 11 (type II), 17 to 20 (type II') and 23 to 26 (type II). The average root-mean-square deviation of the individual NMR conformers relative to their mean co-ordinates is 0.38 A for the backbone atoms and 0.77 A for all heavy atoms of these residues. Increased structural disorder was found for the N-terminal dipeptide segment, the loop at residues 31 to 36, and the C-terminal tripeptide segment. The solution structure of hirudin(1-51) has the same molecular architecture as the corresponding polypeptide segment in natural hirudin and recombinant desulfatohirudin. It is also closely similar to the crystal structure of the N-terminal 51-residue segment of hirudin in a hirudin-thrombin complex, with root-mean-square deviations of the crystal structure relative to the mean solution structure of 0.61 A for the backbone atoms and 0.91 A for all heavy atoms of residues 3 to 30 and 37 to 48. Further coincidence is found for the loop formed by residues 31 to 36, which shows increased structural disorder in all available solution structures of hirudin, and of which residues 32 to 35 are not observable in the electron density map of the thrombin complex. Significant local structural differences between hirudin(1-51) in solution and hirudin in the crystalline thrombin complex were identified mainly for the N-terminal tripeptide segment and residues 17 to 21. These are further analyzed in an accompanying paper.

Fibrinolytic Agents↗
PubMedDate not supplied

[Stereochemical theory of the 3-dimensional structure of globular proteins. I. Highly helical intermediate structures].

The authors analyze the physical prerequisites on which the proposed stereochemical theory of the three-dimensional structure of globular proteins is based. The theory represents a stereochemical modelling of the mechanism of protein self-organization suggested earlier by one of the authors. According to this mechanism, a highly helical intermediate structure(s) is formed at first and then it passes into the native one. In the highly-helical intermediate structure the arrangement of the polypeptide chain in space is the same as in the native structure. These two structures differ mainly by the secondary structure of the chain. The transition into the native structure proceeds under the effect of long-range interactions which transform the excess alpha-helices into beta-structural and irregular conformations. The so-called s-helices are considered (the alpha-helix, whose hydrophobic groups form a separate cluster on its surface). s-Helices can be obtained on the greater part of the polypeptide chain of any globular protein. In the unfolded protein chain they are the most stable and rapidly formed structures. It has been shown that namely s-helices are the initial blocks for the formation of the highly-helical intermediate structure. Stereochemical principles of the s-helix packing that permit to predict the three-dimensional structure of highly helical proteins have been found. According to these principles the highly helical structure represents the packing of hydrophobic surfaces and s-helices. In their turn, hydrophobic surfaces are formed as a result of complementary interaction of borders of hydrophobic clusters of two s-helices according to the "knob-hole" principle.

Models, Chemical↗
PubMed1992

Solution structure of neuronal bungarotoxin determined by two-dimensional NMR spectroscopy: calculation of tertiary structure using systematic homologous model building, dynamical simulated annealing, and restrained molecular dynamics.

Neuronal bungarotoxin has previously been shown, using two-dimensional 1H NMR spectroscopy, to have a triple-stranded antiparallel beta-sheet structure which dimerizes in solution [Oswald, R.E., Sutcliffe, M.J., Bamberger, M., Loring, R.H., Braswell, E., & Dobson, C.M. (1991) Biochemistry 30, 4901-4909]. In this paper, structural calculations are described which use the 582 experimentally measured NOE restraints in conjunction with 27 phi-angle restraints from J-value measurements. The positions of the N-terminal region and C-terminal region were poorly defined in the calculated structures with respect to the remainder of the structure. The region of the structure containing the triple-stranded beta-sheet was, however, well defined and similar to that found in the structure of homologous alpha-bungarotoxin (45% amino acid identity). The experimental restraints did not result in a well-defined dimer interface region because of the small number of NOEs which could be identified in this region. An approach was therefore adopted which produced model structures based to varying degrees on the alpha-bungarotoxin structure. Fourteen different structures were generated in this manner and subsequently used as starting points for refinement using dynamical simulated annealing followed by restrained molecular dynamics. This approach, which combines NMR data and homologous model building, has enabled a family of structures to be proposed for the dimeric molecule. In particular, Phe49 has been identified as possibly playing an important role in dimer formation, this residue in one chain interacting with the corresponding residue in the adjacent chain.

Amino Acid Sequence↗
PubMed1992

Determination of a high-quality nuclear magnetic resonance solution structure of the bovine pancreatic trypsin inhibitor and comparison with three crystal structures.

A high-quality three-dimensional structure of the bovine pancreatic trypsin inhibitor (BPTI) in aqueous solution was determined by 1H nuclear magnetic resonance (n.m.r.) spectroscopy and compared to the three available high-resolution X-ray crystal structures. A newly collected input of 642 distance constraints derived from nuclear Overhauser effects and 115 dihedral angle constraints was used for the structure calculations with the program DIANA, followed by restrained energy minimization with the program AMBER. The BPTI solution structure is represented by a group of 20 conformers with an average root-mean-square deviation (RMSD) relative to the mean solution structure of 0.43 A for backbone atoms and 0.92 A for all heavy atoms of residues 2 to 56. The pairwise RMSD values of the three crystal structures relative to the mean solution structure are 0.76 to 0.85 A for the backbone atoms and 1.24 to 1.33 A for all heavy atoms of residues 2 to 56. Small local differences in backbone atom positions between the solution structure and the X-ray structures near residues 9, 25 to 27, 46 to 48 and 52 to 58, and conformational differences for individual amino acid side-chains were analyzed for possible correlations with intermolecular protein-protein contacts in the crystal lattices, using the pairwise RMSD values among the three crystal structures as a reference.

Amino Acid Sequence↗
PubMed1992

Determination of the nuclear magnetic resonance solution structure of the DNA-binding domain (residues 1 to 69) of the 434 repressor and comparison with the X-ray crystal structure.

The DNA-binding domain of the phage 434 repressor consisting of N-terminal residues 1 to 69 (434 repressor(1-69)), was expressed in Escherichia coli with natural isotope abundance, uniform 15N-labeling and biosynthetically directed fractional 13C-labeling in extent of about 10%. With these protein preparations the three-dimensional structure was determined in solution. The techniques used were nuclear magnetic resonance (n.m.r.) spectroscopy for the collection of conformational constraints, calculation of the protein structure from the n.m.r. data with the program DIANA and structure refinements by restrained energy minimization with a modified version of the program AMBER. A group of 20 conformers characterizes a well-defined structure for residues 1 to 63, with an average of 0-6 A for the root-mean-square deviations (RMSD) calculated for the backbone atoms of the individual conformers relative to the mean co-ordinates. The spatial structure of C-terminal residues 64 to 69 is not defined by the n.m.r. data. The molecular architecture of the 434 repressor(1-69) in solution includes five alpha-helices extending from residues 2 to 13, 17 to 24, 28 to 35, 45 to 52 and 56 to 60, which enclose a well-defined hydrophobic core. The n.m.r. structure is closely similar to the reported crystal structure of the 434 repressor(1-69), with an RMSD value of 1.1 A for the backbone atoms of residues 1 to 63. Small differences between the two structures in regions of the first helix and the loop between helices 3 and 4 were analyzed relative to possible correlations with protein-protein contacts in the crystal lattice and the different milieus of pH and ionic strength in the crystals and n.m.r. samples. Further systematic comparisons of local conformational features indicated that there are correlations between amino acid types, local precision of the structure determination by both techniques and local differences between the structures in the crystals and in solution. Overall, hydrophobic residues are most precisely characterized and agree most closely in the two environments.

Amides↗
PubMed1992

1.67-A X-ray structure of the B2 immunoglobulin-binding domain of streptococcal protein G and comparison to the NMR structure of the B1 domain.

The structure of the B2 immunoglobulin-binding domain of streptococcal protein G has been determined at 1.67-A resolution using a combination of single isomorphous replacement (SIR) phasing and manual fitting of the coordinates of the NMR structure of B1 domain of streptococcal protein G [Gronenborn, A. M., et al. (1991) Science 253, 657-661]. The final R value was 0.191 for data between 8.0 and 1.67 A. The structure described here has 13 residues preceding the 57-residue Ig-binding domain and 13 additional residues following it, for a total of 83 residues. The 57-residue binding domain is well-determined in the structure, having an average B factor of 18.0. Only residues 8-77 could be located in the electron density maps, with the ends of the structure fading into disorder. Like the B1 domain, the B2 domain consists of four beta-strands and a single helix lying diagonally across the beta-sheet, with a -1, +3 chi, -1 topology. This small structure is extensively hydrogen-bonded and has a relatively large hydrophobic core. These structural observations may account for the exceptional stability of protein G. A comparison of the B2 domain X-ray structure and the B1 domain NMR structure showed minor differences in the turn between strands and two and a slight displacement of the helix relative to the sheet. Hydrogen bonds between crystallographically related molecules account for most of these differences.

Amino Acid Sequence↗
PubMed1992

Structural effects induced by mutagenesis affected by crystal packing factors: the structure of a 30-51 disulfide mutant of basic pancreatic trypsin inhibitor.

The X-ray structure of the C30V/C51A disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) has been analyzed at 1.6 A resolution. The mutant crystallizes in a cell having two molecules in the asymmetric unit. The packing environments of these two molecules are quite different, allowing for an assessment of which among the observed structural changes result from the mutation and which are produced by lattice packing considerations. The removal of the 30-51 disulfide bridge has little apparent affect on the B-factors of segments of adjacent polypeptide chain, although there are distinct differences in the structure compared to wild-type BPTI crystal structures. Both of the two C30V/C51A molecules show differences at the mutation site when compared to another 30-51 disulfide mutant, C30A/C51A, presumably due to the larger steric bulk of a valine versus an alanine at residue 30. A comparison of the two independent C30V/C51A molecules indicates that there are significant differences between them even at the site of mutation. The description of the specific structural differences of each molecule differs in detail and suggests different conclusions about the nature of structural perturbation near 30-51. In addition, when these two molecules are compared to two different wild-type structures, which had been determined from different space groups, a somewhat different pattern of changes is observed. These findings indicate that crystal packing can influence the observed perturbations in mutant structures.

Alanine↗
PubMed1992

Structure of a fluid dioleoylphosphatidylcholine bilayer determined by joint refinement of x-ray and neutron diffraction data. III. Complete structure.

We present in this paper the complete structure of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in the L alpha phase (66% RH, 23 degrees C) obtained by the joint refinement of neutron and x-ray lamellar diffraction data. The structural details obtained have previously required a large number of neutron diffraction experiments, using numerous specifically-deuterated phospholipid isomorphs (Büldt et al., 1978. Nature (Lond.). 271:182-184). The joint-refinement approach minimizes specific deuteration by utilizing independent neutron and x-ray data sets. The method yields a quasimolecular structure consisting of a series of multiatomic fragments that are each represented by one or several Gaussian distributions whose positions and widths can be determined to within 0.06 to 0.52 A exclusive of the methylene region. The image of DOPC at 66% RH (5.36 +/- 0.08 waters per lipid) is consistent with many aspects of bilayer structure previously determined by structural and spectroscopic studies. The most striking feature of the structure is the large amount of transbilayer thermal motion suggested by the widths and overlaps of the Gaussian envelopes of the quasimolecular fragments. We discuss the "dynamic bilayer thickness" which describes the minimum effective thickness of the hydrocarbon permeability barrier in terms of the thermal motion of the water. A gradient of thermal motion exists that increases in either direction away from the glycerol backbone which is the most constrained portion of the bilayer. The steric interactions between headgroups of apposed bilayers, expected at the hydration level of our experiments, are clearly revealed. A useful consequence of the quasimolecular structure is that average boundaries within bilayers calculated using composition and volumetric data and ad hoc assumptions can be related to the positions of the principal structural groups. Several measures of "bilayer thickness" in common use can be identified as the positions of the cholines for Luzzati's d1 (Luzzati and Husson. 1962. J. Cell Biol. 12:207-219) and the glycerols for Small's dL (Small. 1967. J. Lipid Res. 8:551-556). We do not know if these relations will be true at other hydrations or for other lipids. Of particular interest is the fact that the position of the carbonyl groups marks the average hydrocarbon/headgroup boundary. It must be emphasized, however, that this region of the bilayer must be generally characterized as one of tumultuous chemical heterogeneity because of the thermal motion of the bilayer.

Biophysical Phenomena↗
PubMed1992

Comparison of the NMR solution structure with the X-ray crystal structure of the activation domain from procarboxypeptidase B.

The NMR solution structure of the activation domain isolated from porcine procarboxypeptidase B is compared with the X-ray crystal structure of the corresponding segment in the intact proenzyme. For the region of the polypeptide chain that has a well-defined three-dimensional structure in solution, i.e., the backbone atoms of residues 11-76 and 25 amino acid side chains in this segment that form a hydrophobic core in the activation domain, the root-mean-square distance between the two structures is 1.1.A. There are no significant differences in average atom positions between the two structures, but only the NMR structure shows increased structural disorder in three outlying loops located along the same edge of the activation domain. These regions of increased structural disorder in the free domain coincide only partially with the interface to the enzyme domain in the proenzyme.

Amino Acid Sequence↗
PubMed1992

Refinement of the crystal structure of ribonuclease S. Comparison with and between the various ribonuclease A structures.

Ribonuclease S (RNase-S) is a complex that consists of two proteolytic fragments of bovine pancreatic ribonuclease A (RNase-A): the S-peptide (residues 1-20) and S-protein (residues 21-124). We have refined the crystal structures of three RNase-S complexes. The first two contain the full-length 20-residue S-peptide and were studied at pHs of 4.75 and 5.5. The third one consists of a truncated form of S-peptide (residues 1-15) and was studied at pH 4.75 as the reference structure for a series of mutant peptide complexes to be reported separately. Excluding residues 16-23 which are either missing (in the S15 complex) or disordered (in both S20 complexes), all three structures refined at 1.6-A resolution are identical within the estimated errors in the coordinates (0.048 A for the backbone atoms). The R-values, residual error, range from 17.4% to 18.6%. The final model of S20, pH 4.75, includes 1 sulfate and 84 water molecules. The side chains of 11 residues were modeled in two discrete conformations. The final structures were independent of the particular RNase-A or RNase-S used as a starting model. An extensive comparison with refined crystal structures of RNase-A reveals that the core of the molecule which is held together with extensive hydrogen bonds is in identical pattern in all cases. However, the loop regions vary from one structure to another and are often characterized by high B-factors. The pattern of thermal parameters appears to be dependent on crystal packing and correlates well with the accessibility calculated in the crystal. Gln60 is a conserved residue in all sequences known to date for this class of ribonucleases. However, it is the only residue that is clearly defined in an unfavorable position (phi = -100 degrees, psi = -130 degrees) on the Ramachandran plot. The origin of the substantial differences between RNase-A and RNase-S in stability to both acid and temperature denaturation and in susceptibility to proteolysis at neutral pH is not obvious in our visual comparison of these two structures.

Animals↗
PubMed1992

Sequence-structure matching in globular proteins: application to supersecondary and tertiary structure determination.

A methodology designed to address the inverse globular protein-folding problem (the identification of which sequences are compatible with a given three-dimensional structure) is described. By using a library of protein finger-prints, defined by the side chain interaction pattern, it is possible to match each structure to its own sequence in an exhaustive data base search. It is shown that this is a permissive requirement for the validation of the methodology. To pass the more rigorous test of identifying proteins that are not close sequence homologs, but that have similar structure, the method has been extended to include insertions and deletions in the sequence, which is compared to the fingerprint. This allows for the identification of sequences having little or no sequence homology to the fingerprint. Examples include plastocyanin/azurin/pseudoazurin, the globin family, different families of proteases and cytochromes, including cytochromes c' and b-562, actinidin/papain, and lysozyme/alpha-lactalbumin. Turning to supersecondary structure prediction, we find that alpha/beta/alpha fragments possess sufficient specificity to identify their own and related sequences. By threading a beta-hairpin through a sequence, it is possible to predict the location of such hairpins and turns with remarkable fidelity. Thus, the method greatly extends existing techniques for the prediction of both global structural homology and local supersecondary structure.

Amino Acid Sequence↗
PubMed1992

Variability of conformations at crystal contacts in BPTI represent true low-energy structures: correspondence among lattice packing and molecular dynamics structures.

The structures of five basic pancreatic trypsin inhibitor (BPTI) molecules are compared to establish the extent and nature of the conformational variability resulting from crystal packing effects. BPTI is an ideal system to evaluate such factors because of the availability of high resolution X-ray models of five different BPTI structures, each in a different crystal packing environment. Differences observed among the structures are found to be distributed throughout the molecule, although the regions that display most variability are associated with the loop structures (residues 14-17 and 24-29). The regions of structure that show the largest rms deviations from the mean of the five packing motifs correlate well with the presence of intermolecular contacts in the crystal lattice. For most of the molecules there is also a correspondence between a larger number of intermolecular contacts and systematically higher B-factors, although it is not apparent whether this is induced by the crystal contact or results from the fact that the contacts are made predominantly through surface loops. The conformational differences seen among the X-ray models constitute more than local shifts at the lattice contact surfaces, and in fact involve in some cases the making and breaking of intramolecular H-bonds. The magnitudes of the differences among packing models are significantly larger than those usually associated with changes induced by mutagenesis; for instance; the structural differences at the site of mutation observed on removing an internal disulfide from the molecule are significantly less than those associated with lattice contact effects. The crystal packing conformations are compared to representative structures of BPTI generated during a 96-psec molecular dynamics (MD) simulation. This comparison shows a high level of correspondence between the protein flexibility indicated by the X-ray and MD analyses, and specifically between those regions that are most variable. This suggests that the regions that show most variability among the crystal packing models are not artifacts of crystallization, but rather represent true low-energy conformers that have been preferentially selected by crystallization factors.

Amino Acid Sequence↗
PubMedDate not supplied

[Investigation of the structure of magnesium and lithium salts of T2 phage DNA by the method of x-ray diffraction. The possible mechanisms of the participation of cations in the structural transformation of double-stranded DNA].

The secondary structure of DNA is known to be largely determined by the kind of counterion bound to it. We have used the X-ray diffraction method to study the structure of magnesium and lithium salts of T2 phage DNA in oriented fibres. The structural behaviour of this glucosylated DNA in the form of magnesium and lithium salts was shown to be identical to the behaviour of the same salts of "normal" calf thymus DNA throughout the studied range of relative humidities (44-95%). However these two DNAs in the form of sodium salt are known to behave quite differently. One can presume that Mg2+ and Li+ influence the structural behaviour of double-stranded DNA so effectively as to be able to "ignore" the fact that T2 phage DNA contains glucoside residues. The results of this work and the already known facts concerning the structure of DNA in the form of various cation salts (in solution and in "solid" fibres) indicate that the structural behaviour of double-stranded DNA is mainly determined by the cation located in the region of the narrow groove of the double helix. If cations are graded according to the efficiency of their influence on the structural behaviour of DNA in fibres, the scale will coincide with that of their DNA-binding strength in water solution, that is: Mg2+ greater than Li+ greater than Na+ greater than K+ greater than Rb+. A qualitative consideration of electrostatic interaction between the cations and the negatively charged DNA strands leads one to suppose that this interaction must obstruct the transition of individual DNA molecules from the B-form to the A-form. Aggregation of self-aggregation of DNA molecules is presumed necessary to enable them to adopt the A-conformation.

Cations, Monovalent↗