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PubMed1993

Computer-assisted molecular modeling: indispensable tools for molecular pharmacology.

Ball-and-stick mechanical models, typically associated with chemists, have been helpful in understanding structural problems and the relationship between structure and biologic activity. With progress in computer speed, graphics performance, and software innovation, molecules of biological interest can be subjected to rigorous calculations. Computational chemistry and biology are rooted in the belief that theoretical physics can be used to calculate accurate molecular structures. Although in its infancy, computer-assisted molecular modeling is gaining attention and acceptability as an increasing number of researchers turn their attention toward rational molecular design. The trend to use theoretical methods can be traced to the greater availability of computer graphics work-stations, decreasing computer costs, faster central processing units, more robust algorithms, and "user-friendly" software codes. Every major pharmaceutical company has invested in these resources to reduce the time it takes to design and develop pharmaceutical agents. Because of the vast financial and manpower investments needed to introduce a single drug, medicinal chemists and pharmacologists are interested in understanding and predicting drug action at the molecular level. Although drug action is still poorly understood, molecular modeling should reduce some of the labor in the development of pharmaceutical agents.

Computer Graphics↗
PubMed2004

The conformation and movement of Na channel inactivation gate peptide in linker between domain III and IV during inactivation by NMR spectroscopy and molecular modeling study.

Amodel peptide that their sequence corresponds to the linker part between domain III and IV of rat brain type IIA Na+ channel has been synthesized for the conformational affect study corresponded to different gated states of Na+ channel. Nuclear magnetic resonance spectra of local anesthetic (LA) diphenyl drugs, such as phenytoin, in presence of a model peptide in both phosphate buffer and phospholipid bicelles (dimyristotl phosphocholine/dihexanoyl phospholcholine), which micelles serve to mimic the peptide-lipid interactions, have been measured to obtain information of the interactions between selected drugs and model peptide. Molecular modeling is performed to help to provide possible conformational information about the polypeptide LIII-IV that may be critical for recognition and signal transduction of inactivated Na+ channel. The voltage-sensing mechanism of Na+ channel involves the movement of the inactivation particles (Ile, Phe, and Met) in the LIII-IV while binding to S4-S5 intracellular region within DIII and DIV. The movement of LIII-IV making its C-terminal residues, including Glu1492 and Glu1493, may aligned near and stabilize the LAs bound with their receptors.

Anesthetics, Local↗
PubMed1997

A binding study of phospholipase A2 with lecithin, lysolecithin and their tetrahedral intermediates using molecular modeling.

We used molecular modeling to examine the binding of 1,2-dioctanoyl-sn-glycero-3-phosphocholine (a lecithin), 1-octanoyl-sn-glycero-3-phosphocholine (a lysolecithin) and their tetrahedral intermediates in the catalytic site of phospholipase A2 (PLA2). We performed energy minimization on each complex, computed the binding energy, determined the relative binding energy among the complexes and calculated the difference in inter- and intramolecular energies of the components in the complexes. We found that the calculated orientation of the sn-1 ester bond of lysolecithin in the active site is similar to that of the sn-2 ester bond in lecithin, thus permitting PLA2 to hydrolyze lysolecithin using the same mechanism as it uses to hydrolyze lecithin. On the other hand, the binding of lecithin is energetically more favorable by 4.5 kcal/mol than the binding of lysolecithin to the enzyme, and the binding of the lecithin tetrahedral intermediate is also energetically more favorable by 19.7 kcal/mol than the binding of the lysolecithin tetrahedral intermediate to the enzyme, which explains why lecithin is a better substrate than lysolecithin in the catalytic site. These results indicate that the activation energy for the hydrolysis of lysolecithin is higher than that for lecithin, consistent with the observed slower rate for the hydrolysis of lysolecithin.

Animals↗
PubMed1994

Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling.

The molecular basis of protein C deficiency was studied in three type I and three type II heterozygotes. Three probands showed thrombotic complications. All the exons and intron/exon junctions of the protein C gene were studied using a strategy combining by the polymerase chain reaction (PCR) amplification, single-strand conformational polymorphism (SSCP) analysis, and DNA sequencing of the PCR-amplified fragments. Six missense mutations were identified, including three novel ones. One was located in exon II, in which the initiating translation codon (ATG) encoding for Met at position -42 was replaced by ACG encoding for Thr. The other five were located in exon IX, and included TAC(Tyr399)-->CAC(His), CCG(Pro327)-->CTG(Leu), GAC(Asp359)-->AAC(Asn) in two cases, and GGG(Gly350)-->AGG(Arg). Four of the six missense mutations occurred in CG dinucleotide. Sequence analysis of the other exons excluded additional mutations. By restriction enzyme analysis, co-segregation of the mutation with protein C deficiency was observed in four families. The other two mutations at amino acid positions -42 and 350 were also considered to be associated with protein C deficiency due to the absence of these mutations in 50 normal individuals. A structural model of the protease domain of mutant activated protein C was constructed by the chimeric modelling method, and the resultant model suggested conformational changes due to each missense mutation identified in protein C deficiency. The present data also provide some evidence regarding the genetic heterogeneity of protein C deficiency.

Adult↗
PubMed2001

alpha-, beta-, and gamma-Cyclodextrin dimers. Molecular modeling studies by molecular mechanics and molecular dynamics simulations.

The alpha-, beta-, and gamma-cyclodextrin (CyD) dimers have been studied by molecular mechanics (MM) and molecular dynamics (MD) calculations, and the relative stability of dimers and the involved molecular interactions have been determined. Three possible orientations were considered for the alpha-, beta-, and gamma-CyD dimers: the head-to-head, the head-to-tail, and the tail-to-tail. In vacuo MM calculations were used to obtain the most stable arrangements, and MD simulations were performed over all energy minima obtained for each dimer. Results from MD always show head-to-head orientation as the most stable as a result of the larger number of intermolecular hydrogen bonds present.

Journal Article↗
PubMed1991

Molecular modeling of phytochrome.

Molecular models of phytochrome were generated to gain insight into structure-function relationships of this important, tetrapyrrole-containing plant protein. Molecular dynamics simulation of a 51-amino acid segment surrounding the chromophore attachment site in oat phytochrome (Cys-321) generated a folded structure. Cys-321 was located within this structure in a beta-turn at the entrance of a distinct pocket. When attached to this amino acid, a semicircular conformation of the Pr chromophore easily fit within the pocket, with the sidechain carboxyl groups in association with Arg and Lys residues in the peptide backbone. Models of Z and E isomers at the C-4 or C-15 double bonds were generated to produce potential conformations of the Pfr chromophore. Comparison of predicted reactivity of the tetrapyrrole, deduced from the models, with that described in the extensive literature on phytochrome clearly indicated that isomerization at C-4 is consistent with experimental data. Isomerization at C-4 caused the chromphore to move partially out of the pocket and brought the sidechain carboxyl groups and ring D to the surface of the polypeptide. This change in orientation is compatible with the observed interaction of Pfr with metal ions, which possibly is a component in the physiological activity of this protein.

Computer Simulation↗
PubMed2002

Molecular modelling in structural biology.

Molecular modelling is a powerful methodology for analysing the three dimensional structure of biological macromolecules. There are many ways in which molecular modelling methods have been used to address problems in structural biology. It is not widely appreciated that modelling methods are often an integral component of structure determination by NMR spectroscopy and X-ray crystallography. In this review we consider some of the numerous ways in which modelling can be used to interpret and rationalise experimental data and in constructing hypotheses that can be tested by experiment. Genome sequencing projects are producing a vast wealth of data describing the protein coding regions of the genome under study. However, only a minority of the protein sequences thus identified will have a clear sequence homology to a known protein. In such cases valuable three-dimensional models of the protein coding sequence can be constructed by homology modelling methods. Threading methods, which used specialised schemes to relate protein sequences to a library of known structures, have been shown to be able to identify the likely protein fold even in cases where there is no clear sequence homology. The number of protein sequences that cannot be assigned to a structural class by homology or threading methods, simply because they belong to a previously unidentified protein folding class, will decrease in the future as collaborative efforts in systematic structure determination begin to develop. For this reason, modelling methods are likely to become increasingly useful in the near future. The role of the blind prediction contests, such as the Critical Assessment of techniques for protein Structure Prediction (CASP), will be briefly discussed. Methods for modelling protein-ligand and protein-protein complexes are also described and examples of their applications given.

Databases, Protein↗
PubMed1996

Lipophilicity in molecular modeling.

PURPOSE: The molecular lipophilicity potential (MLP) offers a three-dimensional representation of lipophilicity, a molecular property encoding intermolecular recognition and intramolecular interactions. METHOD: The interest and applications of the MLP in molecular modeling are varied, as illustrated here. RESULTS: The MLP is a major tool to assess the dependence of lipophilicity on conformation. As a matter of fact, the MLP combined with an exploration of the conformational space of a solute reveals its "chameleonic" behavior, i.e. its capacity to adapt to its molecular environment by hydrophobic collapse or hydrophilic folding. Another successful application of the MLP is its concatenation into 3D-QSAR (Comparative Molecular Field Analysis, CoMFA). CONCLUSION: Work is in progress to expand the MLP into a docking tool in the modeling of ligand-receptor interactions.

Chemical Phenomena↗
PubMed1997

Analysis of a peptide inhibitor of paramyxovirus (NDV) fusion using biological assays, NMR, and molecular modeling.

To investigate the molecular mechanisms involved in paramyxovirus-induced cell fusion, the function and structure of a peptide with a 20-amino-acid sequence from the leucine zipper region (heptad repeat region 2) of the Newcastle disease virus fusion protein (F) were characterized. A peptide with the sequence ALDKLEESNSKLDKVNVKLT (amino acids 478-497 of the F protein) was found to inhibit syncytia formation after virus infection and after transfection of Cos cells with the HN (hemagglutinin-neuraminidase) and F protein cDNAs. Using an F protein gene that requires addition of exogenous trypsin for cleavage, it was shown that the peptide exerted its inhibitory effect prior to cleavage. The three-dimensional conformation of the peptide in aqueous solution was determined through the use of NMR and molecular modeling. Results showed that the peptide formed a helix with properties between an alpha-helix and a 3(10)-helix and that leucine residues aligned along one face of the helix. Side chain salt bridges and hydrogen bonds likely contributed to the stability of the peptide secondary structure. Analysis of the aqueous solution conformation of the peptide suggested mechanisms for specificity of interaction with the intact F protein.

Amides↗
PubMed1991

MULTI: a shared memory approach to cooperative molecular modeling.

A general purpose molecular modeling system, MULTI, based on the UNIX shared memory and semaphore facilities for interprocess communication is described. In addition to the normal querying or monitoring of geometric data, MULTI also provides processes for manipulating conformations, and for displaying peptide or nucleic acid ribbons, Connolly surfaces, close nonbonded contacts, crystal-symmetry related images, least-squares superpositions, and so forth. This paper outlines the basic techniques used in MULTI to ensure cooperation among these specialized processes, and then describes how they can work together to provide a flexible modeling environment.

Computer Communication Networks↗
PubMed1963

Molecular model for protein synthesis.

Molecular models constructed for RNA, adapter RNA, and the ribosome are consistent with available physical-chemical data. These components can be assembled to produce a stereochemically sound model for the template mechanism in protein synthesis.

Models, Molecular↗
PubMed2004

Origin of spontaneous polarization, tilt, and chiral structure of smectic liquid-crystal phases composed of bent-core molecules: a molecular model.

A simple molecular model is proposed for novel bent-core smectic phases that enables one to explain the origin of the experimentally observed chiral structure of the B2 phase composed of nonchiral banana-shaped molecules. It is shown that in the perfectly ordered smectic phase the distributed dispersion interaction between banana-shaped molecules stabilizes the spontaneous polarization and may be responsible for the tilt of the director. The orientation of the spontaneous polarization with respect to the tilt plane is determined by the balance between the dispersion and electrostatic dipole-dipole intermolecular interactions. In particular, sufficiently strong dipole-dipole interaction promotes the B2 phase where the polarization is normal to the tilt plane. The actual chiral structure of each smectic layer in the B2 phase appears as a result of the symmetry breaking. In the case of small molecular dipoles the nonchiral polar smectic phase is formed where the spontaneous polarization is parallel to the tilt plane. The role of the opening angle and of the axial ratio of banana-shaped molecules is also considered and a phase diagram is presented.

Journal Article↗
PubMed1995

A model of the active site of dipeptidyl peptidase IV predicted by comparative molecular field analysis and molecular modelling simulations.

A molecular model of the active site of the serine protease dipeptidyl peptidase IV (DPP IV or CD26) has been developed on the basis of comparative molecular field analysis (CoMFA) of competitive inhibitors and by force field calculations. By application of CoMFA experimentally obtained inhibition constants Ki have been successfully predicted. The resulting steric and electrostatic coefficients of CoMFA were used for the development of the molecular model. The main assumptions of the model are the recognition of substrates or inhibitors by the side chains of a tyrosine (S1-position) and a tryptophan residue (S2-position). The model helps us to understand a multitude of experimental data regarding the substrate specificity of this enzyme as well as results obtained by genetic engineering experiments by other authors. General conclusions concerning a new family of serine proteases are drawn and discussed.

Binding Sites↗
PubMed2003

Nanoscopic structure of a metallo-supramolecular polyelectrolyte--amphiphile complex, elucidated by X-ray scattering and molecular modeling.

A combination of molecular modeling and X-ray scattering was used to elucidate the structure of the metallosupramolecular polyelectrolyte--amphiphile complex (PAC) self-assembled from FeII, 1,4-bis(2,2':6,'2"-terpyridin-4'-yl)benzene, and dihexadecyl phosphate (DHP). An approximate structure of the semi-ordered material was derived from the analysis of the X-ray scattering data. The experimental data provided sufficient input for obtaining a useful starting configuration for molecular modeling. Various models of the supramolecular architecture are presented and discussed in terms of their total energies and scattering patterns. In an iterative approach each level of the structural hierarchy was refined until satisfactory agreement of calculated and experimental scattering patterns was reached. The remarkable sensitivity of the simulated scattering curves to even the smallest structural changes at all length scales restricts the arbitrariness of modeling. The final model of PAC consists of flat lamellae of alternating strata of interdigitated DHP monolayers and nematically ordered polyelectrolyte chains.

Journal Article↗
PubMed2002

Molecular modeling study of the norfloxacin-DNA complex.

Molecular modeling and molecular dynamics were performed to investigate the interaction of norfloxacin with the DNA oligonucleotide 5'-d(ATACGTAT)(2). Eight quinolone-DNA binding structures were built by molecular modeling on the basis of experimental results. A 100ps molecular dynamics calculation was carried out on two groove binding models and six partially intercalating models. The resulting average structures were compared with each other and to free DNA structure as a reference. The favorable binding mode of norfloxacin to a DNA substrate was pursued by structural assess including steric hindrance, presence of hydrogen-bonding, non-bonding energies of the complex and presence of abnormal structural distortion. Although two of the intercalative models showed the highest binding energy and the lowest non-bonding interaction energy, they presented structural features which contrast with experimental results. On the other hand, one groove binding model demonstrated the most acceptable structure when the experimental observation was accounted. In this model, hydrogen bonding of the carbonyl and carboxyl group of the norfloxacin rings with the DNA bases was present, and norfloxacin binds to the amine group of the guanine base which protrudes toward the minor groove of B-DNA.

Binding Sites↗
PubMed2004

Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling.

Conformations of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative were determined in various solvents. The experimental NMR data--coupling constants and NOE contacts--were compared with the results of molecular modelling--molecular mechanics calculations and molecular dynamics simulations. The conformational changes, on the right-hand side of the 14-membered ring, affected mostly the 3JH2,H3 values and NOE crosspeaks H3 or H4 to H11. Oleandomycin was found to be present predominantly in the C3-C5 folded-in conformations in DMSO-d6 solution, whereas in buffered D2O, acetone-d6 and CDCl3, there was a mixture of folded-in and folded-out conformational families. The predominant conformation of the 8-methylene-oleandomycin-9-oxime derivative in solution was a folded-out one although different amounts of folded-in conformation were also present depending on the solvent. Oleandrose and desosamine sugar moieties adopted the usual and expected chair conformation. The conformation around the glycosidic bonds, governing the relative orientation of sugars vs. the lactone ring, showed a certain flexibility within two conformationally close families. We believe that by combining the experimental NMR data and the molecular modelling techniques, as reported in this paper, we have made significant progress in understanding the conformational behaviour and properties of macrolides. Our belief is based on our own current studies on oleandomycins as well as on the previously reported results and best practices concerning other macrolides. A rational for macrolide conformational studies and advances in methodology has been suggested accordingly.

Carbon Isotopes↗