O. Tapia

Self-consistent reaction field theory of solvent effects

A quantum-mechanical reaction field theory of solvent effects is proposed. It contains as a limiting case Onsagers model. It leads to an effective, non-linear, hamiltonian for the molecule in solution and hence to a tool for studying changes in charge distributions and molecular properties. Numerical examples are given.

Solvent effect theories: Quantum and classical formalisms and their applications in chemistry and biochemistry

The quantum chemical and mathematical background and some new approaches to the modeling of solvent effects are described.

Molecular volumes and surfaces of biomacromolecules via GEPOL: a fast and efficient algorithm

A triangular tesselation approach to build up surfaces has been adapted to the study of biomolecules. By using a data-coded generic pentakisdodecahedron each atom is assigned a particular sphere whose radii are chosen according to any suitable property. Different types of surfaces have been adapted to this method: van der Waals, surface accessible, and Richards molecular surface. A simple method is used to eliminate all triangles found at the intersection volume of the atomic spheres and a fast algorithm is employed to calculate the area of the envelope surface and the volume therein. The data about the surface are given by the coordinates of the center of each triangle, elementary surface value, and vector coordinates of the normal to the surface. Color coding of standard properties such as charge densities, potential energy, or any scalar property can be easily done with standard graphics libraries. Fairly detailed information on vector properties, such as electric field and atom velocity, can also be graphically represented by using projections along the normals with adequate color coding.

Surface fractality as a guide for studying protein—protein interactions

Abstract The concept of fractal dimension is applied to protein surfaces. Satellite tobacco necrosis virus, prealhumin, retinol binding protein and lysozyme have been studied. A residue fractal index has been defined, which provides a suitable colour code when using computer graphics for visualizing surfaces. Some provisions are made that render the MS algorithm useful to calculate protein surface fractal dimensions. It has been found that a correlation exists between regions of high fractal dimension and those involved in protein-protein interactions. The usefulness of surface fractality in this context is demonstrated by a molecular docking experiment.

Molecular dynamics simulations of the holo and apo forms of retinol binding protein: structural and dynamical changes induced by retinol removal

The effects of removing retinol from the X-ray structure of holo-retinol binding protein are studied using the molecular dynamics technique. Structural and dynamical properties emerging from an 80 ps simulation of the apo form, for which no crystallographic structure is available, are compared with the results of a 70 ps trajectory of the holo-protein. Dynamical stationarity is attained after roughly 30 ps, and the resulting average structure is proposed as a reasonable model of the apo-protein. Conformational changes are observed for the loops at the beta-barrel entrance during the non-equilibrium part of the apo-trajectory. Tryptophan labelling experiments and retinoid reconstitution experiments point towards this part of the molecule as being involved in prealbumin binding. Structural changes in this region may therefore explain the differences in prealbumin affinity between the apo and holo forms. Furthermore, a change in the position of the alpha-helix, corresponding to a pivot around its C terminus, is observed for the apo-protein. The resulting conformation of the alpha-helix is found to be similar to that in apo-beta-lactoglobulin, which also can bind retinol and for which a crystal structure exists. The results from the holo simulation are compared to the crystallographic data and show good agreement. The dynamics of the secondary and tertiary structural elements are analysed and compared for the two forms. The beta-barrel is found to be extremely cooperative in its atomic motions in both simulations, and the top and bottom beta-sheets perform collective fluctuations with respect to each other in the low-frequency limit of the simulations. The dynamics of the alpha-helical region presents clear differences between the two forms; while the holo-protein has a well-defined spectrum for the longitudinal stretching mode, the apo form displays a fairly large bending of the alpha-helix at several points of the trajectory.

Environmental effects on H-bond potentials: A SCRF MO CNDO/2 study of some model systems☆

Abstract The self-consistent reaction field (SCRF) theory of solvent effects upon dipolar species has been applied to the study of H-bonded systems. A model to represent the enzyme core medium is discussed. It is shown, albeit heuristically, that this type of environment may be represented with the combined effect of a reaction field and an inhomogeneous external electric field acting over the site system, this latter being provided by the main chain dipolar peptide residues. The generalization of the reaction field concept attained within the SCRF theory allowed for this extention to be operationally implemented. The model systems considered are: a formaldehyde-water, acetone-water, a water dimer and a tetrahedrally arranged water trimer. The interest has been focuzed on the study of the dependance upon the site-surrounding coupling strength of the intermolecular potentials and interactions related to the H-bond. The orientational and intermolecular distance dependance of the pair potential and the proton potentials have been considered. The perturbing effect of the enzyme core medium is manifested through the drastic variation of many (but not all) of the H-bond potentials. The changes showed by the orientational component of the intermolecular potential together with that of the proton potential shape illustrate this point. As far as the proton and charge relay mechanisms are concerned, the results reported, while confirming our previous ones, shed a new light upon these matters. The sensitization of the H-bridge towards an external electric field is made possible by the presence of the reaction field, in absence of this latter, the external field effect is not significant.

Hydrogen bond. Environmental effects on proton potential curves. An SCRF MO CNDO/2 calculation of a water dimer

Abstract A solvent and/or environmental effect has been introduced into the MO CNDO/2 calculation of a model hydrogen bonded system. Proton potential curves, potential energy, dipole moments, the polarizability component parallel to the reaction field, and the second order perturbation effects associated to the dispersion forces, have been studied as a function of a solute-solvent coupling parameter. This parameter may be related, through the self-consistent reaction field theory of solvent effects, to both the macroscopic dielectric properties of the solvent and to the local order (if any) around the solute. Numerical results corresponding to a water dimer are discussed.

On the theory of solvent-effect representation: Part I. A generalized self-consistent reaction field theory

Abstract A generalized reaction field theory of surrounding medium effects on the electronic wavefunction of a solute or subsystem immersed therein is proposed. The reaction field (RF) potential is given as a compact functional form factorized into a solute charge density and an RF susceptibility. The latter depends on the geometry and static polarizability distribution of the surrounding medium. For non-homogeneous media, such as protein environments of the active site in enzymes, a permanent electrostatic potential is also present. The scheme is well suited to the study of electronic systems in structurally fluctuating environments when these are simulated either with molecular dynamics or Monte Carlo techniques. Solvent effects on the electronic structure of chemically reacting species can be handled in a straightforward way; this possibility is a result of the form the RF potential acquires in the present treatment.

Enzyme catalysis and transition structures in vacuo. Transition structures for the enolization, carboxylation and oxygenation reactions in ribulose-1,5-bisphosphate carboxylase/oxygenase enzyme (Rubisco)

An extended scheme of enzyme catalysis is presented. This highlights the process of binding leading to activated substrates and requires a detailed knowledge of the transition structure, which is a saddle point of index one on the energy hypersurface, characterizing the chemical interconversion step for the reaction in vacuo. The theory underlying the new scheme goes a step beyond the standard transition-state approach to rate processes. An AM1 characterization is presented of saddle points of index 1 for the enolization carboxylation and oxygenation steps in the molecular reaction mechanism of ribulose-1,5-bisphosphate carboxylase/oxygenase, using 3,4-dihydroxypentan-2-one as substrate model. It is shown that the transition structure of highest energy is for enolization. The successor complex of enolization is a fragment of the precursor complex for carboxylation and oxygenation. The former is in a singlet spin state, the latter is a triplet. Both reactions are ‘inevitable’ once enolization is accomplished in the distorted geometry the fragment has at the active site. Moreover, similar geometric structures are found for the D-ribulose-1,5-bisphosphate (RuBP) moiety in the transition structures of carboxylation and oxygenation showing that the precursor complexes correspond to highly deformed molecular species with respect to the ground-state structures in vacuo. The computed results allow for a simple explanation of Rubiscos bifunctionality.

Computer Assisted Simulations and Molecular Graphics Methods in Molecular Design. 1. Theory and Applications to Enzyme Active-Site Directed Drug Design

A survey is presented of model building techniques, computer-assisted molecular dynamics simulations and a new theory of enzyme catalysis. Some aspects of the theoretical formalism are given. Enzyme active-site directed drug design is illustrated with examples taken from molecular modeling studies using FAD-containing disulphide oxidoreductases, proteinases and carbonic anhydrases.