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E F Meyer

Publications and source records attributed to E F Meyer.

At least 37 records · Page 2Linked to original sources
PubMed1989

Animation: a useful tool for protein molecular dynamicists, applied to hydrogen bonds in the active site of elastase.

Massive amounts of coordinate data result from molecular dynamics calculations. The animation program MDKINO is a simple but powerful tool for previewing or reviewing the results. In recent simulations of elastase, we have examined hydrogen bonding patterns, conformational changes involving shifts in ring positions and rotations of amino acid side chains, electric fields in interatomic space, and electric forces acting on chosen nuclei. Animation is also useful for checking on the stability of calculations in progress. Simple programming techniques achieve acceptable levels of animation with readily available hardware (PS330 or PS390 display with a serial interface to a laboratory VAX). In about half an hour, it is possible to make and watch a color stereo "movie" of a selected subsystem of a simulation (up to 1,000 frames of about 100 atoms each).

Binding Sites↗
PubMed1988

X-ray diffraction analysis of the inhibition of porcine pancreatic elastase by a peptidyl trifluoromethylketone.

X-ray crystallographic data to 2.57 A resolution (1 A = 0.1 nm) have been measured for the complex of a peptidyl trifluoromethylketone inhibitor with porcine pancreatic elastase (PPE); R = 0.14. The inhibitor forms a stable complex with the enzyme by means of a covalent attachment to active site Ser195O gamma, resulting in a hemiketal moiety with tetrahedral geometry. The tripeptide protion binds as an antiparallel beta-sheet, with four hydrogen bonds augmenting the active-site covalent linkage, Ki = 9.5 microM. His57 exhibits a bifurcated H-bond to both Ser195O gamma and an F atom of the inhibitor. This study is one of a series which explores the binding geometry of a variety of small substrates and inhibitors to PPE. This peptidyl-PPE complex affords insight into the binding geometry of a novel trifluoromethylketone moiety to a serine proteinase.

Animals↗
PubMed1988

Analysis of an enzyme-substrate complex by X-ray crystallography and transferred nuclear Overhauser enhancement measurements: porcine pancreatic elastase and a hexapeptide.

The hexapeptide substrate Thr-Pro-nVal-NMeLeu-Tyr-Thr reacts with porcine pancreatic elastase sufficiently slowly that accelerated crystallographic data collection procedures and two-dimensional transferred nuclear Overhauser enhancement measurements could be used to study the geometry of binding. Both studies report a time-averaged population of the Michaelis complex state, prior to proteolysis. This result provides an important data point along the reaction coordinate pathway for serine proteases. Crystallographic data to 1.80-A resolution were used in the structure analysis with refinement to an R-factor of 0.19.

Animals↗
PubMed1987

Energy minimization and molecular dynamics studies of Asn-102 elastase.

Four isomeric forms of the Asn-102 PPE (D102N mutant according to the emerging protocol, [Knowles, Science, 236 (1987) 1252-1258]) have been investigated using energy minimization (EM) and molecular dynamics (MD) techniques. MD simulation data for 175 ps are reported for each form (in total 700 ps for about 2500 atoms). The His-57 N epsilon-protonated forms are calculated to be more stable than the N delta-protonated ones. The active site region of the most stable form is very similar to that found in the D102N rat trypsin enzyme [Craik et al., Science, 237 (1987) 909-913]. Conformations of the active sites and their hydrogen bond patterns are presented for each of these forms and are compared with the structure of the native enzyme active site. The pH dependent activity of the D102N derivative is discussed.

Animals↗
PubMed1986

Stereochemistry of binding of the tetrapeptide acetyl-Pro-Ala-Pro-Tyr-NH2 to porcine pancreatic elastase. Combined use of two-dimensional transferred nuclear Overhauser enhancement measurements, restrained molecular dynamics, X-ray crystallography and molecular modelling.

A nuclear magnetic resonance study of the conformation of the tetrapeptide acetyl-Pro-Ala-Pro-Tyr-NH2 bound to porcine pancreatic elastase is presented. From two-dimensional transferred nuclear Overhauser enhancement measurements, a set of 23 approximate distance restraints between pairs of bound ligand protons, indicative of an extended type structure, is derived. The structure of the bound tetrapeptide is then refined from two different starting structures (an extended beta-strand and a polyproline helix) by restrained molecular dynamics, in which the interproton distances are incorporated into the total energy of the system in the form of effective potentials. Convergence to essentially the same average restrained dynamics structures is achieved. The refined structures are then modelled into the active site of elastase by interactive molecular graphics. The determination of the anchor point of the bound tetrapeptide on the enzyme was aided by a simultaneous crystallographic study which, despite the fact that only electron density for a Pro-X dipeptide fragment was visible, enabled both the approximate position and orientation of binding to be determined. It is found that the tetrapeptide is bound in the S' binding site in the reverse orientation found in other serine protease-inhibitor complexes and is stabilized both by hydrogen-bonding and by van der Waals' interactions.

Animals↗
PubMed1986

Structure of the product complex of acetyl-Ala-Pro-Ala with porcine pancreatic elastase at 1.65 A resolution.

A single crystal of porcine pancreatic elastase was mounted in a thin-walled capillary and allowed to react with acetyl-Ala-Pro-Ala-paranitroanalide. Diffraction data to 1.65 A resolution were measured and the isomorphous structure was solved from the difference Fourier map. The structure contains two surprises. Two molecules of the product: acetyl-Ala-Pro-Ala molecule are bound in the extended binding site. Both molecules are bound backwards with respect to the established mode of peptide binding.

Amino Acid Sequence↗
PubMed1986

Computer aided prediction and evaluation of the tertiary structure for rat elastase II.

Predictive methods have been extended to generate a proposed tertiary structure of rat elastase II on the basis of primary amino acid sequence and structural homologies within the family of mammalian serine proteinases. Force field refinement calculations were used to relax the structure. Structurally conserved molecules of solvation were introduced and the structure was again refined by means of force-field calculations. The resulting structure suggests probable substrate cleavage preferences. An independent statistical analysis of the crystallographically refined structures of serine proteinases (0.01-0.13 A, RMS) shows a close similarity to the final predicted model of rat pancreatic elastase II (0.03-0.14 A, RMS).

Amino Acid Sequence↗
PubMed1984

Structure-activity relationships of sulfonamide drugs and human carbonic anhydrase C: modeling of inhibitor molecules into the receptor site of the enzyme with an interactive computer graphics display.

We have analyzed the molecular interaction of 28 sulfonamide inhibitors with human carbonic anhydrase C (HCAC) using an interactive computer graphic display. Small aromatic sulfonamides gain most of their inhibitory power towards HCAC from the interaction of hydrogen bond acceptors at the para or meta positions with hydrophilic residues of the enzyme. Additional coordinated water molecules stabilize the complexes of heterocyclic sulfonamides (i.e., thiophenes, 1,3-thiazoles, and 1,3,4-thiadiazoles) with HCAC. We propose two different modes of binding of the heterocyclic ring with respect to the active site cleft: the heterocyclic sulfur atom of a 3,4-unsubstituted thiophene approaches the oxygen atom of a coordinated water molecule (sulfur "out"), whereas in 3,4-unsubstituted 1,3,4-thiadiazoles, the sulfur is in contact with a hydrophobic part of the receptor site (sulfur "in"). This proposal is consistent with crystallographic evidence. Sulfonamides with two aromatic or heterocyclic rings also interact with a hydrophobic pocket of the enzyme located greater than 10 A away from the active site metal Zn2+. We also discuss the possibility that the relative inactivity of thiazide diuretics is due to the steric interaction of the ortho chlorine atom with the enzyme receptor cavity.

Binding Sites↗
PubMed1977

The Protein Data Bank. A computer-based archival file for macromolecular structures.

The Protein Data Bank is a computer-based archival file for macromolecular structures. The Bank stores in a uniform format atomic co-ordinates and partial bond connectivities, as derived from crystallographic studies. Text included in each data entry gives pertinent information for the structure at hand (e.g. species from which the molecule has been obtained, resolution of diffraction data, literature citations and specifications of secondary structure). In addition to atomic co-ordinates and connectivities, the Protein Data Bank stores structure factors and phases, although these latter data are not placed in any uniform format. Input of data to the Bank and general maintenance functions are carried out at Brookhaven National Laboratory. All data stored in the Bank are available on magnetic tape for public distribution, from Brookhaven (to laboratories in the Americas), Tokyo (Japan), and Cambridge (Europe and worldwide). A master file is maintained at Brookhaven and duplicate copies are stored in Cambridge and Tokyo. In the future, it is hoped to expand the scope of the Protein Data Bank to make available co-ordinates for standard structural types (e.g. alpha-helix, RNA double-stranded helix) and representative computer programs of utility in the study and interpretation of macromolecular structures.

Computers↗