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PubMed2006

Determination of a hydroxyl conformation in aqueous xylose using neutron scattering and molecular dynamics.

Recently, it was shown using structural neutron diffraction with isotopic substitutions (NDIS) measurements, combined with molecular dynamics simulations, that in an aqueous solution of D-xylose the hydroxyl group on the C4 position does not significantly occupy the position trans to the H4 atom. Here, a similar combination of NDIS and MD studies is described which uses D-xylose deuterated at the C5 position to further characterize this hydroxyl conformation as being trans to the C5 atom, as predicted by constrained MD simulations, confirming the previous study.

Chemistry, Physical↗
PubMed1998

Molecular dynamics study displays near in-line attack conformations in the hammerhead ribozyme self-cleavage reaction.

We have performed molecular dynamics (MD) calculations by using one of the recently solved crystal structures of a hammerhead ribozyme. By rotating the alpha, beta, gamma, delta, epsilon, and zeta torsion angles of the phosphate linkage of residue 17, the nucleobase at the cleavage site was slightly rotated out of the active site toward the solution. Unconstrained MD simulations exceeding 1 ns were performed on this starting structure solvated in water with explicit counter ions and two Mg2+ ions at the active site. Our results reveal that near attack conformations consistently were formed in the simulation. These near attack conformations are characterized by assumption of the 2'-hydroxyl to a near in-line position for attack on the -O-(PO2-)-O- phosphorous. Also during the time course of the MD study, one Mg2+ moved immediately to associate with a pro-R phosphate oxygen in the conserved core region, and the second Mg2+ remained associated with the pro-R oxygen on the phosphate linkage undergoing hydrolysis. These results are in accord with a one-metal ion mechanism of catalysis and give insight into the possible roles of many of the conserved residues in the ribozyme.

Binding Sites↗
PubMed2006

Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor.

AIM: To investigate the dynamic properties of protein-tyrosine phosphatase (PTP) 1B and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTP1B. METHODS: We performed molecular dynamics (MD) simulations using a long time-scale for both PTP1B and PTP1B complexed with the inhibitor SNA, the most potent and selective PTP1B inhibitor reported to date. The trajectories were analyzed by using principal component analysis. RESULTS: Trajectory analyses showed that upon binding the ligand, the flexibility of the entire PTP1B molecule decreases. The most notable change is the movement of the WPD-loop. Our simulation results also indicated that electrostatic interactions contribute more to PTP1B-SNA complex conformation than the van der Waals interactions, and that Lys41, Arg47, and Asp48 play important roles in determining the conformation of the inhibitor SNA and in the potency and selectivity of the inhibitor. Of these, Arg47 contributed most. These results were in agreement with previous experimental results. CONCLUSION: The information presented here suggests that potent and selective PTP1B inhibitors can be designed by targeting the surface residues, for example the region containing Lys41, Arg47, and Asp48, instead of the second phosphate binding site (besides the active phosphate binding site).

Binding Sites↗
PubMed2005

Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor.

S-(+)-Norfenfluramine (SNF)-an active metabolite of the now-banned anorexigen fenfluramine-has been implicated in the drug's appetite-suppressing actions and its life-threatening cardiovascular side effects. SNF reduces appetite through serotonin 5-HT(2C) receptor activation; it causes cardiopulmonary side effects through 5-HT(2B) receptor activation. Thus, we attempted to identify molecular determinants of SNF binding to 5-HT(2B) receptors distinct from those underlying SNF-5-HT(2C/2A) receptor interactions. Mutagenesis implicated Val2.53 in SNF binding to 5-HT(2B) receptors. Ligand docking simulations suggested both Val2.53 gamma-methyl groups form stabilizing van der Waals' (vdW) interactions with the alpha-methyl group of SNF. A V2.53L mutation induced a 17-fold decrease in affinity; molecular dynamics (MD) simulations suggested that this decrease resulted from the loss of one 2.53-alpha-methyl group vdW interaction. Supporting this, 1) the binding of norfenfluramine (NF) analogs lacking an S-(+) alpha-methyl group (RNF and alpha-desmethyl-NF) was less sensitive to the V2.53L mutation, and 2) a V2.53A mutation decreased SNF affinity 190-fold, but decreased RNF and alpha-desmethyl-NF affinities only 16- and 45-fold, respectively. We next addressed whether the alpha-methyl group of SNF contributes to 5-HT(2C/2A) receptor affinity. Removal of the alpha-methyl group (RNF and alpha-desmethyl-NF), which reduced 5-HT(2B) receptor binding 3-fold, did not affect 5-HT(2C/2A) receptor binding. An alpha-ethyl substituent (alpha-ethyl-NF), which decreased 5-HT(2B) receptor affinity 46-fold, reduced 5-HT(2C) and 5-HT(2A) receptor binding by 14- and 5-fold, respectively. Finally, we determined that residue 2.53 affects SNF potency and efficacy at 5-HT(2B) receptors but not at 5-HT(2C) and 5-HT(2A) receptors. In conclusion, vdW interactions between residue 2.53 and the alpha-methyl group of SNF contribute to the ligand's 5-HT(2) receptor subtype-selective pharmacology.

Appetite Depressants↗
PubMed2006

Calculation of the entropy and free energy of peptides by molecular dynamics simulations using the hypothetical scanning molecular dynamics method.

Hypothetical scanning (HS) is a method for calculating the absolute entropy S and free energy F from a sample generated by any simulation technique. With this approach each sample configuration is reconstructed with the help of transition probabilities (TPs) and their product leads to the configuration's probability, hence to the entropy. Recently a new way for calculating the TPs by Monte Carlo (MC) simulations has been suggested, where all system interactions are taken into account. Therefore, this method--called HSMC--is in principle exact where the only approximation is due to insufficient sampling. HSMC has been applied very successfully to liquid argon, TIP3P water, self-avoiding walks on a lattice, and peptides. Because molecular dynamics (MD) is considered to be significantly more efficient than MC for a compact polymer chain, in this paper HSMC is extended to MD simulations as applied to peptides. Like before, we study decaglycine in vacuum but for the first time also a peptide with side chains, (Val)(2)(Gly)(6)(Val)(2). The transition from MC to MD requires implementing essential changes in the reconstruction process of HSMD. Results are calculated for three microstates, helix, extended, and hairpin. HSMD leads to very stable differences in entropy TDeltaS between these microstates with small errors of 0.1-0.2 kcal/mol (T=100 K) for a wide range of calculation parameters with extremely high efficiency. Various aspects of HSMD and plans for future work are discussed.

Chemistry, Physical↗
PubMed1989

A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein. II. Effects of intermolecular interactions on structure and dynamics.

The crystallographic dimer of the C-terminal fragment (CTF) of the L7/L12 ribosomal protein has been subjected to molecular dynamics (MD) simulations. A 90 picosecond (ps) trajectory for the protein dimer, 19 water molecules and two counter ions has been calculated at constant temperature. Effects of intermolecular interactions on the structure and dynamics have been studied. The exact crystallographic symmetry is lost and the atomic fluctuations differ from one monomer to the other. The average MD structure is more stable than the X-ray one, as judged by accessible surface area and energy calculations. Crystal (non-dimeric) interactions have been simulated in another 40 ps trajectory by using harmonic restraints to represent intermolecular hydrogen bonds. The conformational changes with respect to the X-ray structure are then virtually suppressed. The unrestrained dimer trajectory has been scanned for cooperative motions involving secondary structure elements. The intrinsic collective motions of the monomer are transmitted via intermolecular contacts to the dimer structure. The existence of a stable dimeric form of CTF, resembling the crystallographic one, has been documented. At the cost of fairly small energy expenditure the dimer has considerable conformational flexibility. This flexibility may endow the dimer with some functional potential as an energy transducer.

Computer Simulation↗
PubMed2006

Molecular dynamics simulation of nanoparticle self-assembly at a liquid-liquid interface.

We have used molecular dynamics simulations to investigate the in situ self-assembly of modified hydrocarbon nanoparticles (mean diameter of 1.2 nm) at a water-trichloroethylene (TCE) interface. The nanoparticles were first distributed randomly in the water phase. The MD simulation shows the in situ formation of nanoparticle clusters and the migration of both single particles and clusters from the water phase to the trichloroethylene phase, possibly due to the hydrophobic nature of the nanoparticles. Eventually, the single nanoparticles or clusters equilibrate at the water-TCE interface, and the surrounding liquid molecules pack randomly when in contact with the nanoparticle surfaces. In addition, the simulations show that the water-TCE interfacial thickness analyzed from density profiles is influenced by the presence of nanoparticles either near or in contact with the interface but is independent of the number of nanoparticles present. The nanoparticles, water molecules, and TCE molecules all exhibit diffusion anisotropy.

Journal Article↗
PubMed2002

Structural analysis of human CCR2b and primate CCR2b by molecular modeling and molecular dynamics simulation.

CCR2b, a chemokine receptor for MCP-1, -2, -3, -4, plays an important role in a variety of diseases involving infection, inflammation, and/or injury, as well as being a coreceptor for HIV-1 infection. Two models of human CCR2b (hCCR2b) were generated by homology modeling and 1 ns restrained molecular dynamics (MD) simulation. In one only C113-C190 forms a disulfide bond (SS model); in another the potential C32-C277 disulfide bond was formed (2SS model). Analysis of the structures and averaged displacements of Calpha atoms of the N-terminal residues shows that the main differences between the SS and 2SS models lie in a region D25YDYGAPCHKFD36; in the extracellular part of the 2SS model the accessible surfaces of N12, F23, Y26, Y28 and F35 are obviously raised and a more stable H-bond net is formed. The potential energy of the 2SS-water assembly finally fluctuated around -43,020 kJ x mol(-1), which is about 302 kJ x mol(-1) lower than that of the SS-water assembly. All these results suggest that the 2SS model is more favorable. The CCR2b genes of 17 primates were sequenced and four CCR2b models for primates Ateles paniscus (A. pan), Hylobates leucogyneus(H. leu), Papio cynocephalus (P. cyn) and Trachypithecus francoist ( T. fra) were generated based on the 2SS model. A comparison of hCCR2b with primate CCR2b also supports the importance of the region D25YDYGAPCHKFD36. Electrostatic potential maps of human and primate CCR2b all display the dipolar characteristics of CCR2b with the negative pole located in the extracellular part and a strong positive pole in the cytoplasmic part. Based on the CCR2b model, we suggest that the main functional residues fall in the D25YDYGAPCHKFD36 region, and the negative electrostatic feature is a non-specific, but necessary, factor for ligands or gp120/CD4 binding.

Amino Acid Sequence↗
PubMed2005

Unwinding the helical linker of calcium-loaded calmodulin: a molecular dynamics study.

The fold of calmodulin (CaM) consists of two globular domains connected by a helical segment (the linker), whose conformational properties play a crucial role for the protein's molecular recognition processes. Here we investigate the structural properties of the linker by performing a 11.5 ns molecular dynamics (MD) simulation of calcium-loaded human CaM in aqueous solution. The calculations are based on the AMBER force field. The calculated S2 order parameters are in good accord with NMR data: The structure of the linker in our simulations is much more flexible than that emerging from the Homo sapiens X-ray structure, consistently with the helix unwinding observed experimentally in solution. This process occurs spontaneously in a nanosecond timescale, as observed also in a very recent simulation based on the GROMOS force field. A detailed description of the mechanism that determines the linker unwinding is provided, in which electrostatic contacts between the two globular domains play a critical role. The orientation of the domains emerging from our MD calculations is consistent both with former X-ray scattering data and a recent NMR work. Based on our findings, a rationale for the experimentally measured entropy cost associated to binding to the protein's cellular partners is also given.

Binding Sites↗
PubMed2001

The energetic and structural effects of steric crowding in phosphate and dithiophosphinate complexes of lanthanide cations M3+: a computational study.

Metal-ligand binding strength and selectivity result from antagonistic metal-ligand M-L attractions and ligand-ligand L-L repulsions. On the basis of quantum-mechanical (QM) calculations on lanthanide complexes, we show that this interplay determines the binding affinities in the gas phase. In the series of [ML3] complexes (M = La, Eu, and Yb) with negatively charged phosphoryl ligands L- = (MeO)2PO2- and Me2PS2-, the binding energies follow the order Yb3+ > Eu3+ > La3- for a given ligand, and (MeO)2PO2- > Me2PS2- for a given cation. However, adding a neutral LH ligand to [ML3] changes the order to Eu3+ > Yb3+ > La3+ for the oxygen ligand and La3+ > Eu3- > Yb3+ for the sulfur ligand, indicating that steric strain in the first coordination sphere is largest for the smallest cation and for sulfur binding sites. We investigated the question of additional hydration of the [ML3LH] complexes in aqueous solution by molecular dynamics (MD) simulations, using two sets of atomic charges. It was found that pairwise additive potentials overestimate the coordination and hydration numbers of the cations, while adding polarization energy terms for the ligands yields better agreement between QM and MD results and supports the concept of steric strain in the first coordination sphere.

Journal Article↗
PubMed2001

Structural transitions in neutral and charged proteins in vacuo.

In vacuo proteins provide a simple laboratory to explore the roles of sequence, temperature, charge state, and initial configuration in protein folding. Moreover, by the very absence of solvent, the study of anhydrous proteins in vacuo will also help us to understand specific environmental effects. From the experimental viewpoint, these systems are now beginning to be characterized at low resolution. Molecular dynamics (MD) simulations, in combination with tools for protein shape analysis, can complement experiments and provide further insights on the folding-unfolding transitions of these proteins. We review some aspects of this issue by using the results from a detailed MD study of hen egg-white lysozyme. For lysozyme ions, unfolding can be triggered by Coulombic repulsion. In neutral lysozyme, unfolding can be induced by centrifugal forces and also by weakening the monomer-monomer interaction. In both cases, the resulting unfolded transients can be used as initial configurations for relaxation dynamics. All trajectories are analyzed in terms of global molecular shape features of the backbone, including its anisometry and chain entanglement complexity. This strategy allows us to quantify separately the degree of polymer collapse and the evolution of large-scale folding features. Using these last two notions, we discuss some basic questions regarding the nature of the accessible paths associated with unfolding from, and refolding into, compact conformers.

Animals↗
PubMed2005

Molecular dynamics simulations and free energy calculations of base flipping in dsRNA.

The family of adenosine deaminases acting on RNA (ADARs) targets adenosines in RNA that is mainly double stranded. Some substrates are promiscuously deaminated whereas others, such as the mammalian glutamate receptor B (gluR-B) pre-mRNA, are more selectively deaminated. Many DNA/RNA-base modification enzymes use a base flipping mechanism to be able to reach their target base and it is believed that ADARs function in a similar way. In this study we used molecular dynamics (MD) simulations to describe two sites on the gluR-B pre-mRNA, the selectively targeted R/G site and the nontargeted 46 site, in an attempt to explain the substrate specificity. We used regular MD and also a forced base flipping method with umbrella sampling to calculate the free energy of base opening. Spontaneous opening of the mismatched adenosine was observed for the R/G site but not for the 46 site.

Adenosine↗
PubMed2006

Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist.

Recently we predicted the 3D structure of the human beta2-adrenergic receptor (beta2AR) and of the binding site of several agonists and antagonists to beta2AR. These predictions (MembStruk and HierDock) included no explicit water and only a few lipid molecules. Here we include explicit H(2)O and an infinite lipid bilayer membrane in molecular dynamics (MD) simulations of three systems: apo-beta2AR, epinephrine-bound beta2AR, and butoxamine-bound beta2AR (epinephrine is an endogenous agonist, and butoxamine is a beta2AR selective antagonist). The predicted structures for apo-beta2AR and butoxamine-beta2AR are stable in MD, but in epinephrine-beta2AR, extracellular water trickles into the binding pocket to mediate hydrogen bonding between the catechol of epinephrine and Ser-204 on helix 5. The epinephrine-beta2AR structure shows dynamic flexibility with small, piston-like movements of helices 3 and 6 and transient interhelical hydrogen bonding between Ser-165 on transmembrane 4 and Ser-207 on transmembrane 5. These couplings and motions may play a role in protein activation. The apo-beta2AR shows less dynamic flexibility, whereas the antagonist-beta2AR structure is quite rigid. This MD validation of the structure predictions for G protein-coupled receptors in explicit lipid and water suggests that these methods can be trusted for studying the mechanism of activation and the design of subtype-specific agonists and antagonists.

Adrenergic beta-2 Receptor Agonists↗
PubMed2004

Molecular dynamics simulations of peptides from the central domain of smooth muscle caldesmon.

The central domain of smooth muscle caldesmon contains a highly charged region consisting of ten 13-residue repeats. Experimental evidence obtained from the intact protein and fragments thereof suggests that this entire region forms a single stretch of stable alpha-helix. We have carried out molecular dynamics simulations on peptides consisting of one, two and three repeats to examine the mechanism of alpha-helical stability of the central domain at the atomic level. All three peptides show high helical stability on the timescale of the MD simulations. Deviations from alpha-helical structure in all the simulations arise mainly from the formation of long stretches of pi-helix. Interconversion between alpha-helical and pi-helical conformations occurs through insertion of water molecules into alpha-helical hydrogen bonds and subsequent formation of reverse turns. The alpha-helical structure is stabilized by electrostatic interactions (salt bridges) between oppositely charged sidechains with i,i+4 spacings, while the pi-helix is stabilized by i,i+5 salt bridge interactions. Possible i,i+3 salt bridges are of minor importance. There is a strong preference for salt bridges with a Glu residue N-terminal to a basic sidechain as compared to the opposite orientation. In the double and triple repeat peptides, strong i,i+4 salt bridges exist between the last Glu residue of one repeat and the first Lys residue of the next. This demonstrates a relationship between the repetitive nature of the central domain sequence and its ability to form very long stretches of alpha-helical structure.

Calmodulin-Binding Proteins↗
PubMed2006

Modeling protein thermodynamics and fluctuations at the mesoscale.

We use an extended Go model, in unfrustrated and frustrated variants, to study the energy landscape and the fluctuations of a model protein. The model exhibits two transitions, folding and dynamical transitions, when changing the temperature. The inherent structures corresponding to the minima of the landscape are analyzed and we show how their energy density can be obtained from simulations around the folding temperature. The scaling of this energy density is found to reflect the folding transition. Moreover, this approach allows us to build a reduced thermodynamics in the inherent structure landscape. Equilibrium studies, from full molecular dynamics (MD) simulations and from the reduced thermodynamics, detect the features of a dynamical transition at low temperature and we analyze the location and time scale of the fluctuations of the protein, showing the need of some frustration in the model to get realistic results. The frustrated model also shows the presence of a kinetic trap which strongly affects the dynamics of folding.

Computer Simulation↗
PubMed2003

Molecular dynamics simulations of galectin-1-oligosaccharide complexes reveal the molecular basis for ligand diversity.

Galectin-1 is a member of a protein family historically characterized by its ability to bind carbohydrates containing a terminal galactosyl residue. Galectin-1 is found in a variety of mammalian tissues as a homodimer of 14.5-kDa subunits. A number of developmental and regulatory processes have been attributed to the ability of galectin-1 to bind a variety of oligosaccharides containing the Gal-beta-(1,4)-GlcNAc (LacNAc(II)) sequence. To probe the origin of this permissive binding, solvated molecular dynamics (MD) simulations of several representative galectin-1-ligand complexes have been performed. Simulations of structurally defined complexes have validated the computational approach and expanded upon data obtained from X-ray crystallography and surface plasmon resonance measurements. The MD results indicate that a set of anchoring interactions between the galectin-1 carbohydrate recognition domain (CRD) and the LacNAc core are maintained for a diverse set of ligands and that substituents at the nonreducing terminus of the oligosaccharide extend into the remainder of a characteristic surface groove. The anionic nature of ligands exhibiting relatively high affinities for galectin-1 implicates electrostatic interactions in ligand selectivity, which is confirmed by a generalized Born analysis of the complexes. The results suggest that the search for a single endogenous ligand or function for this lectin may be inappropriate and instead support a more general role for galectin-1, in which the lectin is able to crosslink heterogeneous oligosaccharides displayed on a variety of cell surfaces. Such binding promiscuity provides an explanation for the variety of adhesion phenomena mediated by galectin-1.

Computer Simulation↗
PubMed2006

Molecular simulations of outersphere reorganization energies in polar and quadrupolar solvents. The case of intramolecular electron and hole transfer.

Outersphere reorganization energies (lambda) for intramolecular electron and hole transfer are studied in anion- and cation-radical forms of complex organic substrates (p-phenylphenyl-spacer-naphthyl) in polar (water, 1,2-dichloroethane, tetrahydrofuran) and quadrupolar (supercritical CO2) solvents. Structure and charge distributions of solute molecules are obtained at the HF/6-31G(d,p) level. Standard Lennard-Jones parameters for solutes and the nonpolarizable simple site-based models of solvents are used in molecular dynamics (MD) simulations. Calculation of lambda is done by means of the original procedure, which treats electrostatic polarization of a solvent in terms of a usual nonpolarizable MD scheme supplemented by scaling of reorganization energies at the final stage. This approach provides a physically relevant background for separating inertial and inertialless polarization responses by means of a single parameter epsilon(infinity), optical dielectric permittivity of the solvent. Absolute lambda values for hole transfer in 1,2-dichloroethane agree with results of previous computations in terms of the different technique (MD/FRCM, Leontyev, I. V.; et al. Chem. Phys. 2005, 319, 4). Computed lambda values for electron transfer in tetrahydrofuran are larger than the experimental values by ca. 2.5 kcal/mol; for the case of hole transfer in 1,2-dichloroethane the discrepancy is of similar magnitude provided the experimental data are properly corrected. The MD approach gives nonzero lambda values for charge-transfer reaction in supercritical CO2, being able to provide a uniform treatment of nonequilibrium solvation phenomena in both quadrupolar and polar solvents.

Journal Article↗
PubMed2005

Influence of homologous disaccharides on the hydrogen-bond network of water: complementary Raman scattering experiments and molecular dynamics simulations.

A comparative investigation of trehalose, sucrose, and maltose in water solution has been performed using Raman scattering experiments and Molecular Dynamics simulations. From the analysis of the O-H stretching region in the [2500,4000] cm(-1) Raman spectral range, which includes for the first time the contribution of 'free' water, and the statistical distribution of water HB probabilities from MD simulations, this study confirms the privileged interaction of trehalose with water above a peculiar threshold weight concentration of about 30%. The role of the hydration number of sugars--found higher for trehalose--on the destructuring effect of the water hydrogen bond network is also addressed. The analysis of the water O-H-O bending spectral range [1500,1800] cm(-1) reveals a change of the homogeneity of water molecules influenced by sugars, but the three investigated sugars are found to behave similarly.

Computer Simulation↗