Biomedical subjects

E L Mehler

Publications and source records attributed to E L Mehler.

6 recordsLinked to original sources

PubMed1991

Graphical representation of hydrogen bonding patterns in proteins.

A graphical representation of the intramolecular hydrogen bonding in a protein is described, which provides a direct and easily interpretable display of its secondary and tertiary structural elements. The representation is constructed by scanning the coordinate list for all potential proton donor (PD)--proton acceptor (PA) pairs, and any pair which satisfies certain preset distance and angle criteria is classified as being H-bonded. The resulting list of H-bonds is mapped onto an N x N matrix, where N is the number of residues in the protein, by assigning an element ij of the matrix to all the PA-PD pairs between atoms of residues i and j. Subsequently graphical objects are generated for all elements which are labeled as representing one or more H-bonds, and which can then be plotted or displayed in a way analogous to the graphical representation of the distance matrix (DM). In contrast to the DM, the hydrogen bonding matrix (HBM) is sparse, which allows the patterns representing secondary and tertiary structural motifs to be quickly and clearly recognized. In addition, changes in structure are easily identifiable from changes in the H-bonding patterns. The analysis and interpretation of the HBM is discussed using aspartate amino-transferase and calmodulin as examples.

Algorithms↗

PubMed1991

Structural dynamics of calmodulin and troponin C.

We present the results of computational simulation studies of the structures of calmodulin (CAM) and troponin C (TNC). Possible differences between the structures of these molecules in the crystal and in solution were suggested by results from some recent experimental studies, which implied that their conformations in solution may be more compacted than the characteristic dumbbell shape observed in the crystal. The molecular dynamics simulations were carried out with the CHARMM system of programs, and the environment was modeled with a distance-dependent dielectric permittivity and discrete water molecules surrounding the proteins at starting positions identified in the crystals of CAM and TNC. Methods of macromolecular structure analysis, including linear distance plots, distance matrices and a matrix representation of hydrogen bonding, were used to analyze the nature, the extent and the source of structural differences between the computed structures of the molecules and their conformations in the crystal. Following the longest simulation, in which intradomain structure was conserved, the crystallographically observed dumbbell structure of the molecule changed due to a kinking or bending in the region of the central tether helix connecting the two Ca(2+)-binding domains which moved into close proximity. The resulting structure correlates with experimental observations of complexes between CAM and peptides such as melittin and mastoparan. Analysis of the corresponding pair distance distribution functions in comparison to experimental results suggests the dynamic existence of a non-negligible fraction of the compacted structure in aqueous solutions of CAM. In this more nearly globular shape, CAM reveals to the environment two interior pockets that contain a number of hydrophobic residues, in agreement with NMR data suggesting involvement of such residues in the binding of inhibitors and proteins to CAM.

Calcium↗

PubMed1991

Electrostatic effects in proteins: comparison of dielectric and charge models.

Two approaches for calculating electrostatic effects in proteins are compared and ana analysis is presented of the dependence of calculated properties on the model used to define the charge distribution. Changes in electrostatic free energy have been calculated using a screened Coulomb potential (SCP) with a distance-dependent effective dielectric permittivity to model bulk solvent effects and a finite difference approach to solve the Poisson-Boltzmann (FDPB) equation. The properties calculated include shifts in dissociation constants of ionizable groups, the effect of annihilating surface charges on the binding of metals, and shifts in redox potentials due to changes in the charge of ionizable groups. In the proteins considered the charged sites are separated by 3.5-12 A. It is shown that for the systems studied in this distance range the SCP yields calculated values which are at least as accurate as those obtained from solution of the FDPB equation. In addition, in the distance range 3-5 A the SCP gives substantially better results than the FDPB equation. Possible sources of this difference between the two methods are discussed. Shifts in binding constants and redox potentials were calculated with several standard charge sets, and the resulting values show a variation of 20-40% between the 'best' and 'worst' cases. From this study it is concluded that in most applications, changes in electrostatic free energies can be calculated economically and reliably using an SCP approach with a single functional form of the screening function.

Bacterial Proteins↗

PubMed1991

Electrostatic screening in molecular dynamics simulations.

The screened Coulombic potential has been shown to describe satisfactorily equilibrium properties like pK shifts, the effects of charged groups on redox potentials and binding constants of metal ions. To test how well the screening of the electrostatic potential describes the dynamical trajectory of a macromolecular system, a series of comparative simulations have been carried out on a protein system which explicitly included water molecules and a system in vacuo. For the system without solvent the results of using (i) the standard potential form were compared with results of (ii) the potential where the Coulomb term was modified by the inclusion of a distance dependent dielectric, epsilon (r), to model the screening effect of bulk water, and (iii) standard potential modified by reducing the charge on ionized residue side chains. All molecular dynamics simulations have been carried out on bovine pancreatic trypsin inhibitor. Comparisons between the resulting trajectories, averaged structures, hydrogen bonding patterns and properties such as solvent accessible surface area and radius of gyration are described. The results show that the dynamical behaviour of the protein calculated with a screened electrostatic term compares more favourably with the time-dependent structural changes of the full system with explicitly included water than the standard vacuum simulation.

Animals↗

PubMed1990

Comparison of dielectric response models for simulating electrostatic effects in proteins.

Two recent approaches for calculating pK shifts in proteins are compared. The first of these uses Coulomb's law with a distance-dependent dielectric permittivity, epsilon (r), to model the screening effects of the environment, and the second uses a finite difference approach to solve Poisson's equation. It is shown that an explicit form of epsilon (r) which has been fitted to experimentally determined values of the dielectric permittivity in a range from 1 to 21 A can be approximated by a linear form in the functionally significant range of charge separations of approximately 3-10 A, but for distances greater than 10 A the effective permittivity is strongly nonlinear. A statistical analysis of the errors in calculated pK shifts due to electrostatic interactions between charges with separations greater than 10 A shows that there are only marginal differences in reliability between using Coulomb's law with an appropriate form of epsilon (r) or the finite difference approach for solving Poisson's equation. Thus it is concluded that pK shifts can be calculated just as well, and with considerably less effort, using Coulomb's law.

Chemical Phenomena↗

PubMed1987

Electronic determinants of the anti-inflammatory action of benzoic and salicylic acids.

Ab initio, quantum chemical methods have been used to study the possible modes of binding of benzoic and salicylic acids to cyclooxygenase which lead to their anti-inflammatory action. The biological data for this work were obtained from full dose response curves of the inhibitory potency of active compounds on prostaglandin production in mouse macrophages. With the help of simple regression analysis the most important reactivity indices are identified and the ionization state of the active species is discussed. From the physical significance implied by these regressions and an analysis of the electronic charge distributions of the frontier orbitals, a two-way charge transfer model is proposed. The electrostatic potentials of active and inactive congeners have been analyzed, and it is shown that an electrostatic orientation effect seems to make an important contribution to the binding of the active molecules to their receptor site. An electrostatic potential model of the binding site is proposed, and it is shown that this model is able to rationalize the source of activity or inactivity of the investigated substances.

Animals↗