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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↗
PubMed1999

Molecular dynamics simulations of solvated yeast tRNA(Asp).

Transfer RNA molecules are involved in a variety of biological processes, implying complex recognition events with proteins and other RNAs. From a structural point of view, tRNAs constitute a reference system for studying RNA folding and architecture. A deeper understanding of their structural and functional properties will derive from our ability to model accurately their dynamical behavior. We present the first dynamical model of a fully neutralized and solvated tRNA molecule over a 500-ps time scale. Starting from the crystallographic structure of yeast tRNA(Asp), the 75-nucleotide molecule was modeled with 8055 water molecules and 74 NH4+ counterions, using the AMBER4.1 program and the particle mesh Ewald (PME) method for the treatment of long-range electrostatic interactions. The calculations led to a dynamically stable model of the tRNA molecule. During the simulation, all secondary and tertiary base pairs are maintained while a certain lability of base triples in the tRNA core is observed. This lability was interpreted as resulting from intrinsic factors associated with the "weaker" hydrogen bonding patterns seen in these base triples and from an altered ionic environment of the tRNA molecule. Calculated thermal factors are used to compare the dynamics of the tRNA in solution and in the crystal. The present molecular dynamics simulation of a complex and highly charged nucleic acid molecule attests to the fact that simulation methods are now able to investigate not only the dynamics of proteins, but also that of large RNA molecules. Thus they also provide a basis for further investigations on the structural and functional effects of chemical and posttranscriptionally modified nucleotides as well as on ionic environmental effects.

Base Pairing↗
PubMed2005

Molecular dynamics simulation studies of the conformation and lateral mobility of a charged adsorbate biomolecule: implications for estimating the critical value of the radius of a pore in porous media.

The conformations, the values of the lateral transport coefficient of a charged biomolecule (desmopressin) in the adsorbed layer and in the liquid layers above the adsorbed layer, the potential energies of the interaction between the biomolecules located in different liquid layers with the charged solid surface and with the biomolecules in the adsorbed layer, the potential energies of the interaction between water molecules in the hydration layers surrounding the conformations of the biomolecules in different layers, as well as the structure and number of hydration layers between the different conformations of desmopressin, were determined by molecular dynamics simulation studies. The results show that the lateral mobility of the adsorbed desmopressin is approximately equal to zero and the value of the lateral transport coefficient of the biomolecule in the liquid layers located above the adsorbed layer increases as the distance of the liquid layer from the charged solid surface increases. But the values of the lateral transport coefficient of the biomolecule in the liquid layers above the adsorbed layer are lower in magnitude than the value of the transport coefficient of desmopressin along the direction normal to the charged solid surface in the liquid phase located above the vacant charged sites of the solid surface, and these differences in the values of the transport coefficients have important implications with respect to the replenishment of the biomolecules in the inner parts of a channel (pore), the overall rate of adsorption, and the form of the constitutive equations that would have to be used in macroscopic models to describe the mechanisms of mass transfer and adsorption in the pores of adsorbent media. Furthermore, a novel method is presented in this work that utilizes the information about the sizes of the conformations of the biomolecule in the adsorbed layer and in the liquid layers above the adsorbed layer along the direction that is normal to the charged solid surface, as well as the number and size of the hydration layers along the same direction, and could be used to estimate the value of the lower bound of the linear characteristic dimension of a pore (i.e., pore radius) in porous adsorbent media (e.g., porous adsorbent particles; skeletons of porous monoliths) in order to realize effective transport and overall adsorption rate.

Adsorption↗
PubMed1993

Molecular dynamics simulations provide a structural basis for the experimentally observed nucleotide preferences for DNA interstrand cross-links induced by aziridinylbenzoquinones.

Two-electron reduction of the structurally related aziridinylbenzoquinones DZQ and MeDZQ to their hydroquinone forms, DZHQ and MeDZHQ, respectively, generates species which interact and cross-link DNA at distinct nucleotide sequences. Within single target site duplex oligonucleotides, DZHQ was found to cross-link DNA at 5'-GC-3' and 5'-GNNC-3' sequences, whereas MeDZHQ was found to cross-link predominantly at 5'-GNC-3' within a 5'-GTCA-3' sequence. In a multitarget site duplex oligonucleotide, which contains either the target sequence 5'-TGCAC-3' or 5'-TGCTC-3', DZHQ was found to cross-link at both a 5'-GC-3' (a 1,2 cross-link) and a 5'-GNNC-3' (a 1,4 cross-link) site with approximately equal efficiency. Molecular dynamics simulations were able to accurately reproduce the experimental results and provide a structural basis for the alkylation preferences. Calculations were performed to determine the mobility of the hydroquinone species following guanine N7 (G) alkylation at 5'-TGCAC-3' and 5'-TGTCA-3' sequences. Conformations consistent with the formation of both 1,2 and 1,4 cross-links were observed when DZHQ was placed within a 5-TGCAC-3' sequence. The 1,2 cross-link orientation was more stable and thermodynamically favored. For MeDZHQ at the same site the ligand was unable to form stable 1,2 or 1,4 cross-linking conformations, primarily due to clashes with thymine methyl groups. In contrast, the MeDZHQ monoadduct with a 5'-TGTCA-3' sequence adopted a very stable conformation consistent with formation of a 1,3 cross-link.

Alkylation↗
PubMed2002

Molecular dynamics simulation of the evolution of hydrophobic defects in one monolayer of a phosphatidylcholine bilayer: relevance for membrane fusion mechanisms.

The spontaneous formation of the phospholipid bilayer underlies the permeability barrier function of the biological membrane. Tears or defects that expose water to the acyl chains are spontaneously healed by lipid lateral diffusion. However, mechanical barriers, e.g., protein aggregates held in place, could sustain hydrophobic defects. Such defects have been postulated to occur in processes such as membrane fusion. This gives rise to a new question in bilayer structure: What do the lipids do in the absence of lipid lateral diffusion to minimize the free energy of a hydrophobic defect? As a first step to understand this rather fundamental question about bilayer structure, we performed molecular dynamic simulations of up to 10 ns of a planar bilayer from which lipids have been deleted randomly from one monolayer. In one set of simulations, approximately one-half of the lipids in the defect monolayer were restrained to form a mechanical barrier. In the second set, lipids were free to diffuse around. The question was simply whether the defects caused by removing a lipid would aggregate together, forming a large hydrophobic cavity, or whether the membrane would adjust in another way. When there are no mechanical barriers, the lipids in the defect monolayer simply spread out and thin with little effect on the other intact monolayer. In the presence of a mechanical barrier, the behavior of the lipids depends on the size of the defect. When 3 of 64 lipids are removed, the remaining lipids adjust the lower one-half of their chains, but the headgroup structure changes little and the intact monolayer is unaffected. When 6 to 12 lipids are removed, the defect monolayer thins, lipid disorder increases, and lipids from the intact monolayer move toward the defect monolayer. Whereas this is a highly simplified model of a fusion site, this engagement of the intact monolayer into the fusion defect is strikingly consistent with recent results for influenza hemagglutinin mediated fusion.

Biophysical Phenomena↗
PubMed2004

Molecular dynamics simulation of lipid reorientation at bilayer edges.

Understanding cellular membrane processes is critical for the study of events such as viral entry, neurotransmitter exocytosis, and immune activation. Supported lipid bilayers are commonly used to model these membrane processes experimentally. Despite the relative simplicity of such a system, many important structural and dynamic parameters are not experimentally observable with current techniques. Computational approaches allow the development of a high-resolution model of bilayer processes. We have performed molecular dynamics simulations of dimyristoylphosphatidylcholine (DMPC) bilayers to model the creation of bilayer gaps-a common process in bilayer patterning-and to analyze their structure and dynamics. We propose a model for gap formation in which the bilayer edges form metastable micelle-like structures on a nanosecond timescale. Molecules near edges structurally resemble lipids in ungapped bilayers but undergo small-scale motions more rapidly. These data suggest that lipids may undergo rapid local rearrangements during membrane fusion, facilitating the formation of fusion intermediates thought key to the infection cycle of viruses such as influenza, Ebola, and HIV.

Computer Simulation↗
PubMed2006

On the human CYP2C9*13 variant activity reduction: a molecular dynamics simulation and docking study.

Cytochrome P450 2C9 (CYP2C9) plays a key role in the metabolism of clinical drugs. CYP2C9 is a genetically polymorphic enzyme and some of its allelic variants have less activity compared to the wild-type form. Drugs with a narrow therapeutic index may cause serious toxicity to the individuals who carry such allele. CYP2C9*13, firstly identified by some of the present authors in a Chinese poor metabolizer of lornoxicam, is characterized by mutation encoding Leu90Pro substitution. Kinetic experiments show that CYP2C9*13 has less catalytic activity in elimination of diclofenac and lornoxicam in vitro. In order to explore the structure-activity relationship of CYP2C9*13, the three-dimensional structure models of the substrate-free CYP2C9*1 and its variant CYP2C9*13 are constructed on the basis of the X-ray crystal structure of human CYP2C9*1 (PDB code 1R9O) by molecular dynamics simulations. The structure change caused by Leu90Pro replacement is revealed and used to explain the dramatic decrease of the enzymatic activity in clearance of the two CYP2C9 substrates: diclofenac and lornoxicam. The trans configuration of the bond between Pro90 and Asp89 in CYP2C9*13 is firstly identified. The backbone of residues 106-108 in CYP2C9*13 turns over and their side chains block the entrance for substrates accessing so that the entrance of *13 shrinks greatly than that in the wild-type, which is believed to be the dominant mechanism of the catalytic activity reduction. Consequent docking study which is consistent with the results of the kinetic experiments by Guo et al. identifies the most important residues for enzyme-substrate complexes.

Amino Acid Substitution↗
PubMedDate not supplied

Molecular dynamics simulations of a bacterial autotransporter: NalP from Neisseria meningitidis.

NalP is an autotransporter secretory protein found in the outer membrane of Neisseria meningitidis. The crystal structure of the NalP translocator domain revealed a transmembrane beta-barrel containing a central alpha-helix. The role of this alpha-helix, and of the conformational dynamics of the beta-barrel pore have been studied via atomistic molecular dynamics simulations. Three simulations, each of 10 ns duration, of NalP embedded within a solvated DMPC bilayer were performed. The helix was removed from the barrel interior in one simulation. The conformational stability of the protein is similar to that of other outer membrane proteins, e.g., OmpA, in comparable simulations. The transmembrane beta-barrel is stable even in the absence of the alpha-helix. Removal of the helix results in an influx of water into the pore region, suggesting the helix acts as a 'plug'. Water molecules entering the resultant pore form hydrogen bonds with the barrel lining that compensate for the loss of helix-barrel hydrogen bonds. The dimensions of the pore fluctuate over the course of the simulation revealing it to be flexible, but only wide enough to allow transport of the passenger domain in an unfolded or extended conformation. The simulations help us to understand the role of the central helix in plugging the pore and in maintaining the width of the barrel, and show that the NalP monomer is sufficient for the transport of the passenger domain in an unfolded or extended conformation.

Bacterial Outer Membrane Proteins↗
PubMed2003

Molecular dynamics simulation of the unfolding of the human prion protein domain under low pH and high temperature conditions.

Four 10-ns molecular dynamics (MD) simulations of the human prion protein domain (HuPrP 125-228) in explicit water solution have been performed. Each of the simulations mimicked a different environment of the protein: the neutral pH environment was simulated with all histidine residues neutral and bearing a ND proton and with other titratable side chains charged, the weakly acidic environment was simulated with all titratable side chains charged, the strongly acidic environment was simulated with all titratable side chains protonated. The protein in neutral pH environment was simulated at both ambient (298 K) and higher (350 K) temperatures. The native fold is stable in the neutral pH/ambient temperature simulation. Through out all other simulations, a quite stable core consisted of 10-20 residues around the disulfide bond retain their initial conformations. However, the secondary structures of the protein show changes of various degrees compared to the native fold, parts of the helices unfolded and the beta-sheets extended. Our simulations indicated that the heat-induced unfolding and acid-induced unfolding of HuPrP might follow different pathways: the initial stage of the acid-induced unfolding may include not only changes in secondary structures, but also changes in the tertiary structures. Under the strongly acidic condition, obvious tertiary structure changes take place after 10-ns simulation, the secondary structure elements and the loops becoming more parallel to each other, resulting in a compact state, which was stabilized by a large number of new, non-native side chain-side chain contacts. Such tertiary structure changes were not observed in the higher temperature simulation, and intuitively, they may favor the further extension of the beta-sheets and eventually the agglomeration of multiple protein molecules. The driving forces for this tertiary structure changes are discussed. Two additional 10-ns MD simulations, one with Asp202 protonated and the other with Glu196 protonated compared to the neutral pH simulation, were carried out. The results showed that the stability of the native fold is very subtle and can be strongly disturbed by eliminating a single negative charge at one of such key sites. Correlations of our results with previous experimental and theoretical studies are discussed.

Computer Simulation↗
PubMed2005

Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases.

Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms is a goal that has yet to be achieved. To understand the difference between class I HDAC isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, we have built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3, and HDAC8. Comparison of the homology model of HDAC8 with the recently published X-ray structure shows excellent agreement and validates the approach. A series of HDAC inhibitors were docked to the homology models to understand the similarities and differences between the binding modes. Molecular dynamic simulations of these HDAC-inhibitor complexes indicate that the interaction between the protein surface and inhibitor is playing an important role; also some active site residues show some flexibility, which is usually not included in routine docking protocols. The implications of these results for the design of isoform-selective HDAC inhibitors are discussed.

Amino Acid Sequence↗
PubMed1998

Antagonist profile and molecular dynamic simulation of a Drosophila melanogaster muscarinic acetylcholine receptor.

A stably-transfected, Drosophila cell line (S2-DMl-1) expressing the Drosophila DMl muscarinic acetylcholine receptor (mAChR) exhibits high-affinity, saturable, specific binding of the radiolabelled muscarinic antagonist [3H]-N-methyl scopolamine ([3H]-NMS) with an equilibrium dissociation constant (Kd) of 0.67 +/- 0.02 and a Bmax of 1.53 +/- 0.3 pmol/mg protein. Displacement of [3H]-NMS by mAChR antagonists results in the pharmacological profile: 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > hexahydrosiladifenidol > p-fluorohexahydrosiladifenidol > nitrocaramiphen > pirenzepine > methoctramine > AFDX-116. This antagonist profile most closely resembles that of the vertebrate M3 mAChR subtype. In this study, however, we have demonstrated that the antagonist profile of DM1 is distinct from those of vertebrate mAChR subtypes. Molecular dynamic simulations of the Drosophila muscarinic receptor are presented in the free, carbamylcholine-bound and NMS-bound forms. Theoretical, quantitative structure-activity relationship models have been developed; a good correlation is observed between the interaction energies of the minimized ligand-receptor complexes and the pharmacological affinities of the antagonists tested.

Animals↗
PubMed2004

Molecular dynamics simulations of DNA curvature and flexibility: helix phasing and premelting.

Recent studies of DNA axis curvature and flexibility based on molecular dynamics (MD) simulations on DNA are reviewed. The MD simulations are on DNA sequences up to 25 base pairs in length, including explicit consideration of counterions and waters in the computational model. MD studies are described for ApA steps, A-tracts, for sequences of A-tracts with helix phasing. In MD modeling, ApA steps and A-tracts in aqueous solution are essentially straight, relatively rigid, and exhibit the characteristic features associated with the B'-form of DNA. The results of MD modeling of A-tract oligonucleotides are validated by close accord with corresponding crystal structure results and nuclear magnetic resonance (NMR) nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC) structures of d(CGCGAATTCGCG) and d(GGCAAAAAACGG). MD simulation successfully accounts for enhanced axis curvature in a set of three sequences with phased A-tracts studied to date. The primary origin of the axis curvature in the MD model is found at those pyrimidine/purine YpR "flexible hinge points" in a high roll, open hinge conformational substate. In the MD model of axis curvature in a DNA sequence with both phased A-tracts and YpR steps, the A-tracts appear to act as positioning elements that make the helix phasing more precise, and key YpR steps in the open hinge state serve as curvature elements. Our simulations on a phased A-tract sequence as a function of temperature show that the MD simulations exhibit a premelting transition in close accord with experiment, and predict that the mechanism involves a B'-to-B transition within A-tracts coupled with the prediction of a transition in key YpR steps from the high roll, open hinge, to a low roll, closed hinge substate. Diverse experimental observations on DNA curvature phenomena are examined in light of the MD model with no serious discrepancies. The collected MD results provide independent support for the "non-A-tract model" of DNA curvature. The "junction model" is indicated to be a special case of the non-A-tract model when there is a Y base at the 5' end of an A-tract. In accord with crystallography, the "ApA wedge model" is not supported by MD.

Base Sequence↗
PubMed2003

Assessment by molecular dynamics simulations of the structural determinants of DNA-binding specificity for transcription factor Sp1.

The DNA-binding domain (DBD) of the ubiquituous transcription factor Sp1 consists of three consecutive zinc fingers that recognize a number of nucleotide sequences different from, but related to and sometimes overlapping, those recognized by the structurally better characterized early growth response protein 1 (EGR1, also known as Zif268, Krox-24, and NGFI-A). The accepted consensus binding sequence for Sp1 is usually defined by the asymmetric hexanucleotide core GGGCGG but this sequence does not include, among others, the GAG (=CTC) repeat that constitutes a high-affinity site for Sp1 binding to the wt1 promoter. Since no 3D structure of the whole DBD of Sp1 is available, either alone or in complex with DNA, a homology-based model was built and its interaction with two DNA 14-mers was studied using nanosecond molecular dynamics simulations in the presence of explicit water molecules. These oligonucleotides represent Sp1 target sites that are present in the promoters of the mdr1 and wt1 genes. For comparative purposes and validation of the protocol, the complex between the DBD of EGR1 and its DNA target site within the proximal mdr1 promoter was simulated under the same conditions. Some water molecules were seen to play an important role in recognition and stabilization of the protein-DNA complexes. Our results, which are supported by the available experimental evidence, suggest that the accuracy in the prediction of putative Sp1-binding sites can be improved by interpreting a set of rules, which are a blend of both stringency and tolerance, for the juxtaposed triplet subsites to which each zinc finger binds. Our approach can be extrapolated to WT1 and other related natural or artificial zinc-finger-containing DNA-binding proteins and may aid in the assignment of particular DNA stretches as allowed or disallowed-binding sites.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Conformation of [8-arginine]vasopressin and V1 antagonists in dimethyl sulfoxide solution derived from two-dimensional NMR spectroscopy and molecular dynamics simulation.

Structural and dynamic properties of [8-arginine]vasopressin and a class of highly potent vasopressin V1 antagonists which contain 3-mercapto-3,3-cyclopentamethylene propionic acid (Mca) in position 1 of the vasopressin sequence have been determined. On the basis of two-dimensional NMR experiments in dimethyl sulfoxide solution, interproton distances were derived according to which model conformations were built and refined using molecular dynamics simulations. The conformation of vasopressin and the V1 antagonists differ mainly in the region of the mutated residue. The antagonistic property was found to be related to an inversed chirality of the disulfide bridge. In all investigated molecules, characteristic beta-turn structure elements were found for the backbone conformation of the endocyclic residues Tyr2-Asn5. For this portion of the peptide sequence, various conformational equilibria were detected which matched different time scales. For [Arg8]vasopressin, averaged NMR parameters were obtained which could be explained by rapid interconversion between different beta-turn geometries, whereas multiple slowly exchanging conformations were observed for the V1 antagonists. V1 antagonists containing sarcosine in position 7 exhibited multiple spectral patterns for the exocyclic part attributed to cis/trans isomerization. The X-ray structure of deamino-oxytocin [Wood, S. P., Tickle, I. J., Treharne, A. M., Pitts, J. E., Mascarenhas, Y., Li, J. Y., Husain, J., Cooper, S., Blundell, T. L., Hruby, V. J., Buku, A., Fischman, A. J. & Wyssbrod, H. R. (1986) Science 232, 633-636] was found to represent one sample of the conformational space covered by the multiple conformations found for [Mca1, Arg8]vasopressin.

Amino Acid Sequence↗
PubMed1996

Demonstration that 1-trans-epoxysuccinyl-L-leucylamido-(4-guanidino) butane (E-64) is one of the most effective low Mr inhibitors of trypsin-catalysed hydrolysis. Characterization by kinetic analysis and by energy minimization and molecular dynamics simulation of the E-64-beta-trypsin complex.

1-trans-Epoxysuccinyl-L-leucylamido(4-guanidino)butane (E-64) was shown to inhibit beta-trypsin by a reversible competitive mechanism; this contrasts with the widely held view that E-64 is a class-specific inhibitor of the cysteine proteinases and reports in the literature that it does not inhibit a number of other enzymes including, notably, trypsin. The K1, value (3 x 10(-5) M) determined by kinetic analysis of the hydrolysis of N alpha-benzoyl-L-arginine 4-nitroanilide in Tris/HCl buffer, pH 7.4, at 25 degrees C, I = 0.1, catalysed by beta-trypsin is comparable with those for the inhibition of trypsin by benzamidine and 4-aminobenzamidine, which are widely regarded as the most effective low Mr inhibitors of this enzyme. Computer modelling of the beta-trypsin-E64 adsorptive complex, by energy minimization, molecular dynamics simulation and Poisson-Boltzmann electrostatic-potential calculations, was used to define the probable binding mode of E-64; the ligand lies parallel to the active-centre cleft, anchored principally by the dominant electrostatic interaction of the guanidinium cation at one end of the E-64 molecule with the carboxylate anion of Asp-171 (beta-trypsin numbering from Ile-1) in the S1-subsite, and by the interaction of the carboxylate substituent on C-2 of the epoxide ring at the other end of the molecule with Lys-43; the epoxide ring of E-64 is remote from the catalytic site serine hydroxy group. The possibility that E-64 might bind to the cysteine proteinases clostripain (from Clostridium histolyticum) and alpha-gingivain (one of the extracellular enzymes from phyromonas gingivalis) in a manner analogous to that deduced for the beta-trypsin-E-64 complex is discussed.

Amino Acid Sequence↗
PubMed2006

Binding of novel azole-bridged dinuclear platinum(II) anticancer drugs to DNA: insights from hybrid QM/MM molecular dynamics simulations.

Dinuclear Pt-containing compounds might be used to overcome the intrinsic and acquired cell resistance of widely used anticancer drugs such as cisplatin. Recently, the complexes [[cis-Pt(NH3)2]2(mu-OH)(mu-pz)](NO3)2 (with pz = pyrazolate) (1), [[cis-Pt(NH3)2]2(mu-OH)(mu-1,2,3-ta-N(1),N(2))](NO3)2 (with ta = 1,2,3-triazolate) (2), and the binding of 1 to d(CpTpCpTpG*pG*pTpCpTpCp) have been characterized. Here we provide the structural and electronic properties of the free drugs, of the intermediates of binding to guanine bases, and of the products, by performing DFT calculations. Our results show that in 2 an isomerization of the Pt-coordination sphere from N(2) to N(3) of the triazolate unit determines a thermodynamic stabilization of approximately 20 kcal/mol as a consequence of the formation of an allylic structure. In addition, hybrid quantum-classical molecular dynamics simulations of 1 and 2 DNA adducts have shed light on the structural distortions that the drugs induce to the DNA duplex. Our calculations show that the rise and the tilt of the two adjacent guanines are identical in the presence of 1 and 2, but they markedly increase when 2 binds in the N(1),N(3) fashion. In addition, the drugs do not provoke any kink upon binding to the double-stranded DNA, suggesting that they may act with a mechanism different than that of cisplatin. The accuracy of our calculations is established by a comparison with the NMR data for the corresponding complex with 1.

Algorithms↗
PubMed2003

A dynamic structure for the acyl-enzyme species of the antibiotic aztreonam with the Citrobacter freundii beta-lactamase revealed by infrared spectroscopy and molecular dynamics simulations.

Infrared difference spectra show that at least 4 conformations coexist for the ester carbonyl group of the stable acyl-enzyme species formed between the antibiotic aztreonam and the class C beta-lactamase from Citrobacter freundii. A novel method for the assignment of the bands that arise from the ester carbonyl group has been employed. This has made use of the finding that the infrared absorption intensity of aliphatic esters is surprisingly constant, so a direct comparison with simple model esters has been possible. This has allowed a clear distinction to be made between ester and amide (protein) absorptions. The polarity of the conformer environment varies from hexane-like to strongly hydrogen-bonded. We assume that the conformer with the lowest frequency (1,690 cm(-)(1)) and hence the strongest hydrogen-bonding is the singular conformer observed in the X-ray crystallographic structure, since a good interaction via two hydrogen bonds with the oxyanion hole is seen. Molecular dynamics simulation by the method of locally enhanced sampling revealed that the motion of the ester carbonyl of the acyl-enzyme species in and out of the oxyanion hole is facile. The simulation revealed two pathways for this motion that would go through intermediates that first break one or the other of the two hydrogen bonds to the oxyanion hole, prior to departure of the carbonyl moiety out of the active site. It is likely that such motion for the acyl-enzyme species might also occur with more typical beta-lactam substrates for beta-lactamases, but their detection in the more rapid time scale may prove a challenge.

Acylation↗
PubMed1994

Molecular dynamics simulation of a leucine zipper motif predicted for the integrase of human immunodeficiency virus type 1.

We have used the molecular dynamics (MD) simulation package AMBER4 to search the conformation of a peptide predicted as a leucine zipper motif for the human immunodeficiency virus type 1 integrase protein (HIV IN-LZM). The peptide is composed of 22 amino acid residues and its location is from Val 151 to Leu 172. The searching procedure also includes two known alpha-helices that served as positive controls--namely, a 22-residue GCN4-p1 (LZM) and a 20-residue poly (L-alanine) (PLA). A 21-residue peptide extracted from a cytochrome C crystal (CCC-t) with determined conformation as a beta-turn is also included as a negative control. At the beginning of the search, two starting conformations--namely, the standard right-handed alpha-helix and the fully stretched conformations--are generated for each peptide. Structures generated as standard alpha-helix are equilibrated at room temperature for 90 ps while structures generated as a fully stretched one are equilibrated at 600 K for 120 ps. The CCC-t and PLA helices are nearly destroyed from the beginning of equilibration. However, for both the HIV IN-LZM and the GCN4-p1 LZM structures, there is substantial helicity being retained throughout the entire course of equilibration. Although helix propagation profiles calculated indicate that both peptides possess about the same propensity to form an alpha-helix, the HIV IN-LZM helix appears to be more stable than the GCN4-p1 one as judged by a variety of analyses on both structures generated during the equilibration course. The fact that predicted HIV IN-LZM can exist as an alpha-helix is also supported by the results of high temperature equilibration run on the fully stretched structures generated. In this run, the RMS deviations between the backbone atoms of the structures with the lowest potential energy (PE) identified within every 2 ps and the structure with the lowest PE searched in the same course of simulation are calculated. For both the HIV IN-LZM and the GCN4-p1 LZM, these rms values decrease with the decrease of PE, which indicates that both structures are closer in conformations as their PEs are moved deeper into the PE well.

Amino Acid Sequence↗