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PubMed1999

A new Hybrid Monte Carlo algorithm for protein potential function test and structure refinement.

A new Hybrid Monte Carlo (HMC) algorithm has been developed to test protein potential functions and, ultimately, refine protein structures. The main principle of this algorithm is, in each cycle, a new trial conformation is generated by carrying out a short period of molecular dynamics (MD) iterations with a set of random parameters (including the MD time step, the number of MD steps, the MD temperature, and the seed for initial MD velocity assignment); then to accept or reject the new conformation on the basis of the Metropolis criterion. The novelty in this paper is that the potential in MD iterations is different from that in the MC step. In the former, it is a molecular mechanics potential, in the latter it is a knowledge-based potential (KBP). Directed by the KBP, the MD iteration is used to search conformational space for realistic conformations with low KBP energy. It circumvents the difficulty in using KBP functions directly in MD simulation, as KBP functions are typically incomplete, and do not always have continuous derivatives required for the calculation of the forces. The new algorithm has been tested in explorations of conformational space. In these test calculations the KBP energy was found to drop below the value for the native conformation, and the correlation between the root mean square deviation (RMSD) and the KBP energy was shown to be different from the test results in other references. At the present time, the algorithm is useful for testing new KBP functions. Furthermore, if a KBP function can be found for which the native conformation has the lowest energy and the energy/RMSD correlation is good, then this new algorithm also will be a tool for refinement of the theory-based structural models.

Algorithms↗
PubMed1999

Ranking ligand binding affinities with avidin: a molecular dynamics-based interaction energy study.

The binding of 14 biotin analogues to avidin is examined to evaluate the viability of calculating binding free energy based on molecular dynamics (MD) trajectories. Two approaches were investigated in this work. The first one uses the linear interaction energy approximation, while the other approach utilizes the interaction free energy. The results obtained from these two methods were found to correlate well with the experimental binding free energy data for 10 out of 14 ligands. For the other four ligands, both methods overestimate their binding strength by more than 7 kcal/mol. Free energy calculations using the thermodynamic integration method are employed to understand this overestimation. The effect of protein flexibility on binding free energy calculation and the effect of charged or neutral ligands on the calculated results are discussed. MD simulations are shown to be able to provide insight into the interactions occurring in the active site and the origins of variations in binding free energy.

Avidin↗
PubMed1999

Beta-peptides: twisting and turning.

Oligomers of beta-amino acids (beta-peptides), which are readily available by standard meth ods either in solution or on solid support, adopt a large variety of different secondary structures in solution and in the solid state. beta-Peptides 4, 5 and 10 fold into a helix with 3 residues per turn and 14-membered H-bonded rings (314 helix) that is left-handed for 5 and 10 and right-handed for 2 (due to the reversal of the chirality of the building blocks), as was clearly demonstrated by two-dimensional NMR-spectroscopy. This helix thermally is very stable in methanol solution upon heating. As shown by NMR- and CD-spectroscopy, it is partially populated even at 100 C (Figure 3). Another helix was dis covered for mixed beta-peptide 8 in methanol solution: it is characterized by 12- and 10- membered turns (Figure 4, left) and its central 10-membered turn has been found in the solid state of a geminally disubtituted beta-peptide (Figure 4, right). This central 10-membered turn was used as a scaffold to attach beta-amino acid residues that prefer a linear (non-helical) conformation (beta-peptide 21): a hairpin (pleated sheet-turn-pleated sheet) structure was determined in solution by NMR-spectroscopy (Figure 5). In contrast to this antiparallel pleated-sheet, a parallel pleated sheet was found for a beta-tripeptide in the solid state. For the first time it was possible to observe reversible peptide folding in MD simulations by studying beta-peptides (Figure 6) and to determine folding pathways and intermediates. beta-Peptides are a new class of promising peptidomimetics. They are resistant against the degradation by proteolytic enzymes such as pepsin, elastase, carboxypeptidase A, pro nase or proteasom 20S. A variety of beta-amino acids (27-34) was shown to be non- mutagenic by Ames tests and beta-peptides 47 and 48 reveal large elimination half-lives of 3 h (for 47) and 10 h (for 48) in the serum of rodents (Figure 7). Conjugates of alpha- and beta- peptides are efficient ligands for the HLA*B27 MHC Class I protein, a five fold increase of binding (2.0 microM for 55) compared to a natural peptidic ligand 51 was observed. Furthermore, beta-peptides are able to mimic natural a-peptidic hormones such as somatostatin. The cyclo-beta-tetrapeptide 57 binds to the five human somatostatin receptors in the micromolar range. In addition, several other non-natural oligomers such as beta-peptide nucleic acids (built from 58 and 59), beta-peptoids (60), oligomers of anthranilic acids and beta-sulfonamido peptides are discussed.

Animals↗
PubMed2000

Theoretical models of interactions between buspirone analogues and 5-HT1A and 5-HT2A serotonin receptor subtypes.

In present study the structure-selectivity relationship of buspirone and six of its analogues towards 5-HT1A and 5-HT2A serotonin receptors was investigated on molecular level. Molecular mechanics energy minimisation and advanced molecular dynamics (MD) simulations allowed us to perform a dynamic structural analysis of transmembrane helical domains of the human 5-HT1A and 5-HT2A receptors and investigate the ligand-induced changes of the entire structure of the ligand-receptor complex. The obtained results suggest, that helical and extracellular domains of both receptors have different topography of the putative binding sites and also different dynamical behaviour. The results of this study are consistent with experimental site-directed mutagenesis data and binding affinities of examined ligands towards both serotonin receptors.

Binding Sites↗
PubMedDate not supplied

Recognition of cyclooxygenase-2 (COX-2) active site by NSAIDs: a computer modelling study.

The energetics and models of COX-2 complexed with nonsteroidal anti-inflammatory drugs (NSAIDs) having different degrees of selectivity for two isoforms of COX (COX-2 and COX-1) have been studied using computer modelling approach. The models are obtained for complexes of NS398 (NS), a selective COX-2 inhibitor; indoprofen (Ind), a non-selective inhibitor; di-tert-butylbenzofurans (DHDMBFs) with substituents at the 5th position: CONH(CH2)2OMe (BF1), CONH-c-Pr (BF2), 3-methylene-gamma-butyrolactonyl (BF3) and oxicams namely, meloxicam (Mel), piroxicam (Pir) and tenoxicam (Ten). These were optimized using molecular mechanics (MM) and molecular dynamics (MD) techniques. The binding energies and structures were compared with pharmacological parameters and available results with COX-1. In case of NS a larger difference in the binding energies between COX-2 and COX-1 was noticed as compared to that of Ind. It also had stronger interaction with His90 and Tyr355 which is considered important for COX-2 selectivity. There was a difference in the compactness at the channel entrance between COX-2 selective and non-selective ligands. Models with DHDMBFs and oxicams showed a similar correlation. The results were used to design a peptide inhibitor, Tyr-Arg-Cys-Ala-delta Phe-Cys (Pept) which could fit better in the COX-2 cavity. As per our MD simulation results this peptide inhibitor showed both higher activity and COX-2 selectivity.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

12-O-retinoylphorbol-13-acetate (RPA) behaves like a retinoid-derivative in binding to retinol-binding-protein: a correlation with its specific action as an incomplete tumor promoter?

12-O-retinoylphorbol-13-acetate (RPA), an incomplete tumor promoter of the phorbol ester type and protein kinase C (PKC) activator, consists of two characteristic structural elements: the phorbol body and the retinoyl ester chain. Therefore, possible binding of the incomplete tumor promoter RPA to the human transport protein retinol-binding-protein (RBP) has been examined by molecular modeling methods and experimental binding studies. The calculated prediction of binding properties was primarily based on a comparative geometrical approach. It was shown that the beta-ionone-ring of RPA was not altered within the binding pocket of RBP (molecular modeling) compared to retinoic acid (X-ray crystallographic data). The torsion angle C5'-C6'-C7'-C8', determining the conformation of the RBP-beta-ionone-ring relative to the isoprene tail, is rotated by 42 degrees for RPA compared to retinol and to retinoic acid, respectively. Combining all the results from force field calculations, MD simulations and geometrical comparisons, the conclusion could be drawn that RPA should be able to bind to RBP. This interaction should be less strong than that with its natural ligand retinol or with retinoic acid. This prediction was proven experimentally. RPA was able to compete with retinoic acid for binding at RBP in human plasma. The binding properties were investigated using 3H-labeled retinoic acid in homologous and heterologous competition studies in a one-dimensional native polyacrylamide gel electrophoresis system. An approximately 2000-fold weaker binding of RPA to RBP as compared to retinoic acid was determined experimentally, confirming the prediction of the molecular modeling approach. The characteristic behaviour of RPA as an incomplete promoter, due to possible binding to PKC and RBP, is discussed.

Actins↗
PubMedDate not supplied

Structure of valinomycin by molecular dynamics studies.

Valinomycin is an important ionophore which exhibits a high conformational flexibility. The study of various conformations adopted by this molecule together with the study of flexibility in a given conformation can throw light on the ion transport by the ionophore across the membrane. Molecular dynamics (MD) studies are ideal to characterize the flexibility in different parts of the molecule and can also give an idea of various conformations adopted by the molecule at a given temperature. Hence MD studies at 100K have been carried out on the minimized crystal structure of the molecule to scan the possible conformations in the neighbourhood of the well known 'bracelet' like structure of uncomplexed Valinomycin, Properties, like the flexibility, average values, r.m.s. fluctuations of the various intramolecular hydrogen bonds are discussed. Energy minimization has been carried out on selected MD simulated points to analyze the characteristics of the unique conformation adopted by this molecule at this temperature.

Hydrogen Bonding↗
PubMed1994

The pseudo-beta I-turn. A new structural motif with a cis peptide bond in cyclic hexapeptides.

Synthesis and conformational analysis of three cyclic hexapeptides cyclo(-Gly1-Pro2-Phe3-Val4-Xaa5-Phe6), Xaa = Phe (I), D-Phe (II) and D-Pro (III), were carried out to examine the influence of proline on the formation of reverse turns and the dynamics of hydrophobic peptide regions. Assignment of all 1H and 13C resonances was achieved by homo- and heteronuclear 2D-NMR techniques (TOCSY, ROESY, HMQC, HMQC-TOCSY and HMBCS-270). The conformational analysis is based on interproton distances derived from ROESY spectra and homo- and heteronuclear coupling constants (E.COSY, HETLOC and HMBCS-270). For structural refinements restrained molecular dynamics (MD) simulations in vacuo and in DMSO were performed. Each peptide exhibits two conformations in DMSO solution due to cis-trans isomerism about the Gly-Pro peptide bond. Surprisingly the cis-Gly-Pro segment in the minor isomers is not involved in a beta VI-turn, but forms a turn structure with cis-Gly-Pro in the i and i + 1 positions. Although no stabilizing hydrogen bond is found in this turn, the phi- and psi-angles closely correspond to a beta I-turn [Pro2: phi(i + 1) -60 degrees, psi(i + 1) -30 degrees; Phe3: phi(i + 2) -100 degrees, psi(i + 2) -50 degrees]. Hence we call this structural element a pseudo-beta I-turn. As expected, in the dominating all-trans isomers proline occupies the i + 1 position of a standard beta I-turn. Therefore, cis-trans isomerization of the Gly1-Pro2 amide bond only induces a local conformational rearrangement, with minor structural changes in other parts of the molecule. However, the geometry of the other regions is affected by the chirality of the i + 1 amino acid for both isomers (beta I for Phe5, beta II' for D-Phe5 or D-Pro5).

Computer Simulation↗
PubMed1995

Relationships between conformational behaviour and binding affinity towards beta 1 and beta 2 adrenoceptors of some chiral phenoxypropanolamines with bulky N-substituents.

The optical isomers of a series of phenoxypropanolamine compounds with N-substituents bulkier than isopropyl have been synthesized, and their binding affinity towards beta 1 and beta 2-adrenoceptors has been determined. A computational study, including a Molecular Dynamics (MD) simulation and quenching in water and a GRID analysis provided some useful suggestions for possible interpretation patterns for the different affinity exhibited by the compounds studied.

Computer Simulation↗
PubMed1998

Structural and enzymatic studies of a new analogue of coenzyme B12 with an alpha-adenosyl upper axial ligand.

A new analogue of coenzyme B12 (5'-deoxyadenosylcobalamin, AdoCbl), in which the configuration of the N-glycosidic bond in the Ado ligand is inverted [(alpha-ribo)AdoCbl], has been synthesized and its crystal structure determined by X-ray diffraction [MoKalpha, lambda = 0.71073 A, monoclinic P212121, a = 16.132(12) A, b = 21. 684(15) A, c = 27.30(3) A, 9611 independent reflections, R1 = 0. 0708]. As suggested by molecular mechanics modeling before the structure was known, the Ado ligand lies over the southern quadrant of the molecule, as is the case for AdoCbl. The most striking feature of the structure is disorder in the orientation of the adenine (Ade) moiety relative to the ribose of the Ado ligand. This was resolved with a two-state model in which in the major (0.57 occupancy) conformer the A16(O)-A11-A9(N)-A8 dihedral angle is 1.9 degrees and the Ade is virtually perpendicular to the corrin ring; in the minor conformer, the Ade is tilted down, and this dihedral is -48.7 degrees. The Co-C and axial Co-N bond lengths and the Co-C-C bond angle are quite similar to those in AdoCbl. The corrin ring is considerably flatter than that of AdoCbl, with a fold angle of 11.7 degrees. The molecule was successfully modeled by molecular mechanics (MM), and rotation of the Ado ligand relative to the corrin gave rise to four locally minimum structures with the Ado in the southern, eastern, northern, or western quadrant, with the southern conformation as the global minimum, as is the case with AdoCbl itself. Nuclear Overhauser effects (nOe's) observed by two-dimensional (2D) NMR were incorporated as restraints in molecular dynamics (MD) and simulated annealing (SA) calculations. A MD simulation at 300 K showed that only the southern conformation is populated with the Ado ligand confined to an arc from over C15 to over C12, while the Ade ring oscillates from perpendicular to parallel to the corrin ring. Twenty-seven structures were collected by MD-SA. Most of these annealed into the southern conformation, but examples of the other conformations were also found. The new analogue is a partially active coenzyme for the ribonucleotide reductase from Lactobacillus leichmanii with maximal activity that is 9.7% of that of AdoCbl itself, and a very high Km value (245 microM compared to 0.54 microM for AdoCbl). In addition, the rate constant for enzyme-induced carbon-cobalt bond cleavage of (alpha-ribo)AdoCbl is 160-fold smaller than that for AdoCbl, and only 1/3 as much cob(II)alamin is produced at the active site.

Adenosine↗
PubMed2002

Structure of docosahexaenoic acid-containing phospholipid bilayers as studied by (2)H NMR and molecular dynamics simulations.

Polyunsaturated phospholipids are known to be important with regard to the biological functions of essential fatty acids, for example, involving neural tissues such as the brain and retina. Here we have employed two complementary structural methods for the study of polyunsaturated bilayer lipids, viz. deuterium ((2)H) NMR spectroscopy and molecular dynamics (MD) computer simulations. Our research constitutes one of the first applications of all-atom MD simulations to polyunsaturated lipids containing docosahexaenoic acid (DHA; 22:6 cis-Delta(4,7,10,13,16,19)). Structural features of the highly unsaturated, mixed-chain phospholipid, 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC), have been studied in the liquid-crystalline (L(alpha)) state and compared to the less unsaturated homolog, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The (2)H NMR spectra of polyunsaturated bilayers are dramatically different from those of less unsaturated phospholipid bilayers. We show how use of MD simulations can aid in interpreting the complex (2)H NMR spectra of polyunsaturated bilayers, in conjunction with electron density profiles determined from small-angle X-ray diffraction studies. This work clearly demonstrates preferred helical and angle-iron conformations of the polyunsaturated chains in liquid-crystalline bilayers, which favor chain extension while maintaining bilayer flexibility. The presence of relatively long, extended fatty acyl chains may be important for solvating the hydrophobic surfaces of integral membrane proteins, such as rhodopsin. In addition, the polyallylic DHA chains have a tendency to adopt back-bended (hairpin-like) structures, which increase the interfacial area per lipid. Finally, the material properties have been analyzed in terms of the response of the bilayer to mechanical stress. Simulated bilayers of phospholipids containing docosahexaenoic acid were less sensitive to the applied surface tension than were saturated phospholipids, possibly implying a decrease in membrane elasticity (area elastic modulus, bending rigidity). The above features distinguish DHA-containing lipids from saturated or monounsaturated lipids and may be important for their biological modes of action.

Computer Simulation↗
PubMed2006

Analyzing solution-phase time-resolved x-ray diffraction data by isolated-solute models.

Extracting transient structural information of a solute from time-resolved x-ray diffraction (TRXD) data is not trivial because the signal from a solution contains not only the solute-only term as in the gas phase, but also solvent-related terms. To obtain structural insights, the diffraction signal in q space is often Fourier sine transformed (FT) into r space, and molecular dynamics (MD) simulation-aided signal decomposition into the solute, cage, and solvent terms has so far been indispensable for a clear-cut assignment of structural features. Here we present a convenient method of comparative structural analysis without involving MD simulations by incorporating only isolated-species models for the solute. FT is applied to both the experimental data and candidate isolated-solute models, and comparison of the correlation factors between the experimental FT and the model FTs can distinguish the best candidate among isolated-solute models for the reaction intermediates. The low q region whose influence by solvent-related terms is relatively high can be further excluded, and this mode of truncated Fourier transform (TFT) improves the correlation factors and facilitates the comparison. TFT analysis has been applied to TRXD data on the photodissociation of C(2)H(4)I(2) in two different solvents (methanol and cyclohexane), HgI(2) in methanol, and I(3) (-) in methanol excited at 267 nm. The results are consistent with previous conclusions for C(2)H(4)I(2) in methanol and HgI(2) in methanol, and the new TRXD data reveal that the C(2)H(4)I transient radical has a bridged structure in cyclohexane and I(3) (-) in methanol decomposes into I+I(2) (-) upon irradiation at 267 nm. This TFT method should greatly simplify the analysis because it bypasses MD simulations.

Journal Article↗
PubMed2006

Charge structure and counterion distribution in hexagonal DNA liquid crystal.

A hexagonal liquid crystal of DNA fragments (double-stranded, 150 basepairs) with tetramethylammonium (TMA) counterions was investigated with small angle neutron scattering (SANS). We obtained the structure factors pertaining to the DNA and counterion density correlations with contrast matching in the water. Molecular dynamics (MD) computer simulation of a hexagonal assembly of nine DNA molecules showed that the inter-DNA distance fluctuates with a correlation time around 2 ns and a standard deviation of 8.5% of the interaxial spacing. The MD simulation also showed a minimal effect of the fluctuations in inter-DNA distance on the radial counterion density profile and significant penetration of the grooves by TMA. The radial density profile of the counterions was also obtained from a Monte Carlo (MC) computer simulation of a hexagonal array of charged rods with fixed interaxial spacing. Strong ordering of the counterions between the DNA molecules and the absence of charge fluctuations at longer wavelengths was shown by the SANS number and charge structure factors. The DNA-counterion and counterion structure factors are interpreted with the correlation functions derived from the Poisson-Boltzmann equation, MD, and MC simulation. Best agreement is observed between the experimental structure factors and the prediction based on the Poisson-Boltzmann equation and/or MC simulation. The SANS results show that TMA is too large to penetrate the grooves to a significant extent, in contrast to what is shown by MD simulation.

Computer Simulation↗
PubMed2002

Effects of the nonimmobilizer hexafluroethane on the model membrane dimyristoylphosphatidylcholine.

BACKGROUND: Nonimmobilizers are agents that lack anesthetic properties, although their chemical structure is very similar to known anesthetics. The primary action site of both agents, whether at the membrane or target protein level, is still a matter of debate. However, increasing evidence points to the distinct modifications of the membrane physical properties that such agents induce. Such modification may play a role in the mechanism of anesthesia, and may therefore be related to the differences in their clinical behavior. METHODS: Molecular dynamics (MD) computer simulations have been used to investigate the distribution of a nonimmobilizer, hexafluroethane (HFE, C(2)F(6)), in a lipid membrane. The biologically relevant liquid-crystal phase of a hydrated dimyristoyl phosphatidyl choline (DMPC) bilayer was used as a membrane model. Two MD simulations corresponding to HFE mole fractions of 6% and 25% have been performed at room temperature and constant ambient pressure, for a duration of 2 nanoseconds each. RESULTS: The equilibrium configurations of HFE in the bilayer show that the nonimmobilizer molecules are evenly distributed along the lipid hydrocarbon chains with a slight preference for the bilayer center. This partitioning induces an expansion of the bilayer thickness and a lateral contraction of the membrane (decrease of the area per lipid). The presence of HFE has essentially no effect on the lipid acyl chain conformations in agreement with nuclear magnetic resonance (NMR) measurements of the chain order parameters. The partitioning of the nonimmobilizer does not influence the orientation of the lipid head-group dipole moment. CONCLUSIONS: The modifications induced by the presence of the nonimmobilizer HFE on a model membrane are distinct from those previously found for halothane (CF(3)CHBrCl), its anesthetic analogue, and appear to result from different distributions in the lipid bilayer. The results of the MD simulations show that (1) the changes in the average area per lipid and in the membrane thickness are opposite for the two agents and (2) HFE induces no change in the lipid head-group orientation, in contrast to halothane. These different effects (1) on the physical properties of the lipid bilayer and (2) on the electrostatic properties of the membrane-water interface may be linked to different clinical effects, and thus might contribute to the mechanism of general anesthesia.

Algorithms↗
PubMed1993

Conformational transitions using molecular dynamics with minimum biasing.

The molecular dynamics algorithm (MD), which simulates intramolecular motions on the subnanosecond timescale, has been modified to allow the investigation of slow conformational transitions that do not necessarily occur spontaneously in MD simulations. The method is designated CONTRA MD (CONformational TRAnsitions by Molecular Dynamics with minimum biasing). The method requires the prior definition of a single conformational variable that is required to vary monotonically from an initial conformation to a final target conformation. The simulation is broken up into a series of short free MD segments, and we determine, after each segment of MD, whether or not the system has evolved toward the final conformation. Those segments that do not move the system in that direction are deleted. Those that do move it toward the final conformation are patched together sequentially to generate a single representative trajectory along the transition pathway. The CONTRA MD method is demonstrated first by application to the simultaneous C2'-endo to C3'-endo repucker and anti to syn N-glycosidic torsion transitions in 2'-deoxyadenosine and then to the large-scale bending in phenylalanine transfer RNA.

Monte Carlo Method↗
PubMed2000

Unfolding of hen egg lysozyme by molecular dynamics simulations at 300K: insight into the role of the interdomain interface.

We present the results of two 1.2 ns molecular dynamics (MD) unfolding simulations on hen egg lysozyme in water at 300K, performed using a new procedure called PEDC (Path Exploration With Distance Constraints). This procedure allows exploration of low energy structures as a function of increasing RMSD from the native structure, and offers especially the possibility of extensive exploration of the conformational space during the initial unfolding stages. The two independent MD simulations gave similar chronology of unfolding events: disruption of the active site, kinking of helix C, partial unfolding of the three-stranded beta-sheet to a two-stranded sheet (during which the helices A, B, and D remain to a great extent native), and finally unfolding of the beta-domain and partial unfolding of the alpha-domain in which hydrophobic clusters persist. We show particularly that the loss of hydrophobic contacts between the beta-sheet turn residues Leu55 and Ile56 and the hydrobic patch of the alpha-domain destabilizes the beta-domain and leads to its unfolding, suggesting that the correct embedding of these residues in the alpha-beta interface may constitute the rate limiting step in folding. These results are in accord with experimental observations on the folding/unfolding behavior of hen egg lysozyme at room temperature. They would also explain the loss of stability and the tendency to aggregation observed for the mutant Leu55Thr, and the slow refolding kinetics observed in the analogous amyloidogenic variant of human lysozyme.

Animals↗
PubMed2001

Spermine: an "invisible" component in the crystals of B-DNA. A grand canonical Monte Carlo and molecular dynamics simulation study.

The association of spermine(4+) (Spm(4+)), Mg(2+) and monovalent (M(+)) ions with DNA in crystal form, have been studied using grand canonical Monte Carlo (GCMC) and molecular dynamics (MD) computer simulations. GCMC calculations were used to calculate the distribution of Spm(4+), Mg(2+), and M(+) between the equilibrating solvent and the DNA crystal under conditions mimicking the crystal-growing protocols reported in a number of recent X-ray diffraction studies of DNA oligomers. The GCMC simulations show that the composition of ions neutralizing the negative charge of DNA can vary in a broad range. The GCMC simulations were used to provide appropriate conditions for subsequent 6 ns constant pressure and temperature MD simulations of DNA in a typical crystalline environment consisting of three DNA double helix decamers in a periodic hexagonal cell, containing 1200 water molecules, eight Spm(4+), 32 Na(+) and four Cl(-) ions. Based on the simulation results, it seems possible to give an explanation why spermine molecules are usually not detected in X-ray studies in spite of their high concentration in the preparatory samples used as the crystallizing agent. It appears that this flexible polyamine molecule has several binding modes, interacting in fairly irregular manner with different sites on DNA and showing no regular ordering in the DNA crystals. Ions of Na(+) and Spm(4+) compete with each other and with water molecules in binding to bases in the minor groove and they influence the structure of the DNA hydration shell in different ways.

Algorithms↗