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Biomedical subjects

B Lesyng

Publications and source records attributed to B Lesyng.

11 recordsLinked to original sources
PubMed1994

Lagrangian molecular dynamics using selected conformational degrees of freedom, with application to the pseudorotation dynamics of furanose rings.

Using internal conformational degrees of freedom for biopolymers as natural variables, and introducing a Lagrangian dynamics approach, one can simulate time-dependent processes over a much longer time scale than in classical Newtonian molecular dynamics (MD) techniques. Two factors contribute to this: a substantial reduction in the number of degrees of freedom and a very large increase in the size of the time step. We present the Lagrangian equations of motion for repuckering transitions in model furanose (F), ribose (R), and 2'-deoxyribose (dR) ring systems using the pseudorotation phase angle as the single dynamic variable. As in most Lagrangian analyses, the effective masses for the R and dR models are dependent on conformation, and we test the behavior of this variable mass (VM) model. Since the variation in effective mass is small, the VM model is compared with a simplified constant mass (CM) model, which is shown to be an excellent approximation. The equations of motion for the CM and VM models are integrated with the leapfrog and the iterative leapfrog algorithms, respectively. The Lagrangian dynamics approach reduces the number of degrees of freedom from about 40 to 1, and allows the use of time steps on the order of 20 fs, about an order of magnitude greater than is used in conventional MD simulations.

Biopolymers↗
PubMed1993

Molecular modeling methods. Basic techniques and challenging problems.

An overview is presented of computer modeling and simulation methods that play an increasing role in drug design: quantum chemical methods, molecular mechanics, molecular dynamics and Brownian dynamics. The application of molecular dynamics for the prediction of thermodynamic properties like free energy differences and binding constants is discussed. The Brownian dynamics method is presented in connection with the calculation of effective electrostatic forces using the Poisson-Boltzmann equation, which allows one to sample ligand-binding geometries and to predict the kinetics of diffusion-limited enzyme reactions. New techniques that have recently been extensively developed, such as the global energy minimization and quantum-classical dynamics methods, are also introduced. The molecular modeling methods are illustrated with selected examples.

Cladribine↗
PubMed1990

Thermodynamic cycle-perturbation study of the binding of trifluoroacetyl dipeptide anilide inhibitors with porcine pancreatic elastase.

The variety of results of crystallographic studies of the serine proteases complexed with isocoumarin inhibitors presents a challenging problem to modeling methods and molecular energetics. Therefore, the thermodynamic cycle-perturbation technique has been used to study a model system of elastase and two peptidic inhibitors. Using the program AMBER, the technique correctly predicts changes of the binding constants for the trifluoroacetyl dipeptide inhibitors in comparison with available experimental (kinetic and crystallographic) data. However, the absolute values obtained are shown to be sensitive to the specific electrostatic interaction potential parameters used in the simulations. The reader and user are cautioned that thermodynamic cycle-perturbation results may be too optimistic by underestimating the accuracy of free energy values. This is especially a matter of concern for those cases where a direct comparison with experimental values is not possible, viz., (1) the stimulation of binding of novel compounds, (2) structurally uncertain binding sites, or (3) structurally different binding modes. With our best 4-31G* ESP (electrostatic potential) charges we were able to reproduce experimentally determined free energy differences (delta delta A) with an accuracy of about 1.5 kcal/mol. Dynamically induced structural changes in the binding site of elastase, and particularly changes in hydrogen-bond patterns of the binding site, are also reported.

Anilides↗
PubMed1990

Dynamic properties of the first enzymatic reaction steps of porcine pancreatic elastase. How rigid is the active site of the native enzyme? Molecular dynamics simulation.

Two molecular dynamics simulations (100 and 50 ps) of native porcine pancreatic elastase i.e., without bound substrate and with the active site hydrated by a dome of water (630 molecules) have been performed. Dynamical properties of the catalytic tetrad have been examined. While relative conformations of the Asp 102, His 57, and Ser 214 are rather stable in time, the side chain of Ser 195 undergoes several conformational changes. No preferences are observed for the formation of a hydrogen bond between the O gamma-H group (Ser 195) and nitrogen N, (His 57). A cluster of ordered water molecules effectively competes with the H-O gamma group (Ser 195) and thereby prevents the formation of this H bond, which is generally agreed to be crucial for catalysis.

Animals↗
PubMed1988

A model for the hydrogen-bond-length probability distributions in the crystal structures of small-molecule components of the nucleic acids.

The probability distributions of the N-H...O = C and O-H...O = C hydrogen-bond lengths observed in the crystal structures of the purines, pyrimidines, nucleosides and nucleotides have been fitted to a one-dimensional hydrogen-bond potential-energy function. In order to obtain a quantitative correspondence between the experimental and theoretical distributions, it is necessary to include with the usual hydrogen-bond-type potential-energy function, an effective crystal-packing force and two thermodynamical parameters of the crystal lattice, the Debye temperature and the Gruneisen constant.

Chemical Phenomena↗
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↗
PubMed1978

Theoretical investigations on the conformation of 1,5,N(4),N(4)-tetramethylcytosine.

Theoretical investigations (Perturbative Configuration Interaction over Localized Orbitals (PCILO) and Intermediate Neglect of Differential Overlap (INDO) methods) of the conformation of tetramethylcystosine, an overcrowded molecule with planar structure, have been carried out. The physical features of rotational bending potentials of the dimethylamino group are discussed. Particularly, the controversial problem concerning the planarity of the molecule is investigated. The obtained results show that the planarity of tetramethylcytosine is an intrinsic property of the molecule. Nevertheless, because of the repulsion between the methyl groups, the planar structure of tetramethylcytosine is slightly destabilized. Further, the functional dependence of the dipole moment of tetramethylcytosine on rotation and bending of the dimethylamino group has been analyzed.

5-Methylcytosine↗
PubMed1975

Barrier to rotation and conformation of the -NR2 group in cytosine and its derivatives. Part II. Experimental and theoretical dipole moments of methylated cytosines.

The dipole moments of several cytosine, methylaminocytosine and dime-thylaminocytosine derivatives with and without an ortho methyl group were determined experimentally in dioxane and benzene. Calculations of total energies and dipole moments were performed by the CNDO/2 and INDO methods for sp2 and sp3 hybridization of exocyclic nitrogen for different values of rotational angle phiC-N. Comparison of the experimental dipole moments with those calculated for the energy minima suggests that the conformation of the dimethylamino group is not planar and differs from that found in cytosine. 1,5,7-Trimethylcytosine, with the dipole moment of 7 Deby units, was considered to be the model compound which closely reproduces the dipole moment of cytosine.

Amines↗
PubMed1975

Barrier to rotation and conformation of the NB2 group in cytosine and its derivatives. Part I. Theoretical study of cytosine.

A theoretical investigation of the conformation of the amino group in cytosine has been performed by the CNDO/2 and INDO methods. The results suggest that from the energetical point of view the conformation of the amino group is not stable in the course of rotation. It changes its hybridization from sp2-like in the planar case to sp3-like in the transition state. The physical basis of the barrier to rotation of this group around the C4-N7 bond are discussed. Some comments on the solvent dependence of the electronic absorption spectra of cytosine are presented.

Amines↗