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PubMed2003

Computational study of ketosteroid isomerase: insights from molecular dynamics simulation of enzyme bound substrate and intermediate.

Delta(5)-3-Ketosteroid Isomerase (KSI) catalyzes the isomerization of 5,6-unsaturated ketosteroids to their 4,5-unsaturated isomers at a rate approaching the diffusion limit. The isomerization reaction follows a two-step general acid-base mechanism starting with Asp38-CO(2)(-) mediated proton abstraction from a sp(3)-hybridized carbon atom, alpha to carbonyl group, providing a dienolate intermediate. In the second step, Asp38-CO(2)H protonates the C6 of the intermediate providing a 4,5-unsaturated ketosteroid. The details of the mechanism have been highly controversial despite several experimental and computational studies of this enzyme. The general acid-base catalysis has been proposed to involve either a catalytic diad or a cooperative hydrogen bond mechanism. In this paper, we report our results from the 1.5 nanosecond molecular dynamics (MD) simulation of enzyme bound natural substrate (E.S) and enzyme bound intermediate (E. In) solvated in a TIP3P water box. The final coordinates from our MD simulation strongly support the cooperative hydrogen bond mechanism. The MD simulation of E.S and E. In shows that both Tyr14 and Asp99 are hydrogen bonded to the O3 of the substrate or intermediate. The average hydrogen bonding distance between Tyr14-OH and O3 becomes shorter and exhibits less fluctuation on E.S --> E. In. We also observe dynamic motions of water moving in and out of the active site in the E.S structures. This free movement of water disappears in the E. In structures. The active site is shielded by hydrophobic residues, which come together and squeeze out the waters from the active site in the E. In complex.

Catalysis↗
PubMed2005

Dynamics and stability of GCAA tetraloops with 2-aminopurine and purine substitutions.

The contributions of various interactions in the GGCGCAAGCC hairpin containing a GCAA tetraloop were studied by computer simulations using the substitutions of functional groups. The guanosine (G) in the first tetraloop position or in the C-G closing base pair was replaced by 2-aminopurine (AP), and the individual tetraloop's adenosines (A) were replaced by purine (PUR). These substitutions eliminated particular hydrogen bonds thought to stabilize the GCAA tetraloop. For each substitution, molecular dynamics (MD) simulations were carried out in an aqueous solution with sodium counterions, using the CHARMM27 force field. The MD simulations showed that the substitutions in the first (G-->AP) and the third (A-->PUR) position of the GCAA tetraloop did not significantly influence the conformation of the hairpin. A long-lived bridging water molecule observed in the GCAA loop was present in both modified loops. The substitutions made in the last loop position (A-->PUR) or in the C-G base pair closing the tetraloop (G-->AP) to some extent influenced the loop structure and dynamics. These loops did not display the long-lived bridging water molecules. When the second A in the GCAA loop was replaced by PUR, the first A in the loop was observed in the anti or in the syn orientation about the glycosyl bond. The G to AP substitution in C-G base pair led to a change of their arrangement from the Watson-Crick to wobble. The MD simulations of the hairpin with C-AP wobble closing base pair showed increased conformational dynamics of the hairpin. The changes of hairpin formation free energy associated with the substitutions of individual bases were calculated by the free energy perturbation method. Our theoretical estimates suggest a larger destabilization for the G to AP substitutions in GCAA loop than for the substitutions of individual A's by PUR, which is in accordance with experimental tendency. The calculations predicted a similar free energy change for G to AP substitutions in the GCAA tetraloop and in the C-G closing base pair.

2-Aminopurine↗
PubMed2005

Molecular dynamics simulations of human butyrylcholinesterase.

Herein, we present results from molecular dynamics (MD) simulations of the human butyrylcholinesterase (BuChE) enzyme in aqueous solution. Two configurations of the unbound form of BuChE differing in the presence or absence of a sodium ion inside the protein gorge were simulated for 10 and 5 ns, respectively. Besides complementing the structural information provided by X-ray data, the MD simulations give insight into the structure of the native BuChE enzyme. For example, it is shown that: the nucleophilic Ser(198) residue and the various binding subsites in the BuChE catalytic cavity are readily accessible from the exterior of the protein; the presence of the sodium ion dynamically explores two different binding sites in the gorge leading to the active site and stabilizes the productive conformation of the Glu(325)/His(438)/Ser(198) catalytic triad; several long-lived water bridges are fully integrated into the architecture of the active site; the positions of the residues at the rim of the gorge region display large deviations with respect to the crystal structure; and two side doors, constituted by residues situated at the tip of the acyl- and Omega-loops, respectively, open wide enough to allow the passage of water molecules. In conclusion, we compare our theoretical results with those from previous work on mouse acetylcholinesterase and discuss their implications for substrate binding and catalysis in BuChE.

Animals↗
PubMed2001

Determination of conformational equilibrium of peptides in solution by NMR spectroscopy and theoretical conformational analysis: application to the calibration of mean-field solvation models.

Peptides occur in solution as ensembles of conformations rather than in a fixed conformation. The existing energy functions are usually inadequate to predict the conformational equilibrium in solution, because of failure to account properly for solvation, if the solvent is not considered explicitly (which is usually prohibitively expensive). NMR data are therefore widely incorporated into theoretical conformational analysis. Because of conformational flexibility, restrained molecular dynamics (with restraints derived from NMR data), which is usually applied to determine protein conformation is of limited use in the case of peptides. Instead, (a) the restraints are averaged within predefined time windows during molecular dynamics (MD) simulations (time averaging), (b) multiple-copy MD simulations are carried out and the restraints are averaged over the copies (ensemble averaging), or (c) a representative ensemble of sterically feasible conformations is generated and the weights of the conformations are then fitted so that the computed average observables match the experimental data (weight fitting). All these approaches are briefly discussed in this article. If an adequate force field is used, conformations with large statistical weights obtained from the weight-fitting procedure should also have low energies, which can be implemented in force field calibration. Such a procedure is particularly attractive regarding the parameterization of the solvation energy in nonaqueous solvents, e.g., dimethyl sulfoxide, for which thermodynamic solvation data are scarce. A method for calibration of solvation parameters in dimethyl sulfoxide, which is based on this principle was recently proposed by C. Baysal and H. Meirovitch (Journal of the American Chemical Society, 1998, Vol. 120, pp. 800--812), in which the energy gap between the conformations compatible with NMR data and the alternative conformations is maximized. In this work we propose an alternative method based on the principle that the best-fitting statistical weights of conformations should match the Boltzmann weights computed with the force field applied. Preliminary results obtained using three test peptides of varying conformational mobility: H-Ser(1)-Pro(2)-Lys(3)-Leu(4)-OH, Ac-Tyr(1)-D-Phe(2)-Ser(3)-Pro(4)-Lys(5)-Leu(6)-NH(2), and cyclo(Tyr(1)-D-Phe(2)-Ser(3)-Pro(4)-Lys(5)-Leu(6)) are presented.

Amino Acid Sequence↗
PubMedDate not supplied

Steric trigger as a mechanism for CB1 cannabinoid receptor activation.

To determine the moiety that behaves as the steric trigger to activate the CB(1) cannabinoid receptor, conformational properties of the nonclassical cannabinoid CP55244, one of the most potent CB(1) receptor agonists, were characterized by conformational analysis, rotational barrier calculations, and molecular dynamics (MD) simulations. It was shown from the present MD simulations that the torsion angles phi1 and phi4 of the C3 side chain showed the most dramatic change when compared with the ground-state receptor-bound conformation, indicating that rotation around these torsion angles is responsible for releasing the ligand strain energy. Multiple stages would be involved in the ligand conformational change. As a molecular mechanism for the ligand-induced CB(1) receptor conformational change, we propose that the C3 side chain serves as the steric trigger, while the ACD-ring moiety of CP55244 serves as the plug. Steric clash with helices within the binding pocket would induce microconformational adaptation within the protein. This mechanism would suggest that rotational flexibility in a ligand may be as important a determinant of agonist activity as the pharmacophoric elements that can be identified.

Binding Sites↗
PubMed2006

Adding salt to an aqueous solution of t-butanol: is hydrophobic association enhanced or reduced?

Recent neutron scattering experiments on aqueous salt solutions of amphiphilic t-butanol by Bowron and Finney [Phys. Rev. Lett. 89, 215508 (2002); J. Chem. Phys. 118, 8357 (2003)] suggest the formation of t-butanol pairs, bridged by a chloride ion via O-H...Cl- hydrogen bonds, leading to a reduced number of intermolecular hydrophobic butanol-butanol contacts. Here we present a joint experimental/theoretical study on the same system, using a combination of molecular dynamics (MD) simulations and nuclear magnetic relaxation measurements. Both MD simulation and experiment clearly support the more classical scenario of an enhanced number of hydrophobic contacts in the presence of salt, as it would be expected for purely hydrophobic solutes. [T. Ghosh et al., J. Phys. Chem. B 107, 612 (2003)]. Although our conclusions arrive at a structurally completely distinct scenario, the molecular dynamics simulation results are within the experimental error bars of the Bowron and Finney data.

Journal Article↗
PubMed2006

Molecular dynamics analysis of the engrailed homeodomain-DNA recognition.

Molecular dynamics (MD) simulations were performed for investigating the role of Gln50 in the engrailed homeodomain-DNA recognition. Employing the crystal structure of free engrailed homeodomain and homeodomain-DNA complex as a starting structure, we carried out MD simulations of: (i) the complex between engrailed homeodomain and a 20 base-pair DNA containing TAATTA core sequence; (ii) the free engrailed homeodomain. The simulations show that homeodomain flexibility does not depend on its ligation state. The engrailed homeodomain shows similar flexibility, and the recognition helix-3 shows very similar characteristic of high rigidity and limited conformational space in two complexation states. At the same time, DNA structure has also no obvious conformational fluctuations. These results preclude the possibility of the side chain of Gln50 forming direct hydrogen bonds to the core DNA bases. MD simulations confirm a few well-conserved sites for water-mediated hydrogen bonds from protein to DNA are occupied by water molecules, and Gln50 interacts with corresponding core DNA bases through water-mediated hydrogen bonds. So Gln50 plays a relatively modest role in determining the affinity and specificity of the engrailed homeodomain. In addition, the electrostatic interaction between homeodomain and phosphate backbone of the DNA is a main factor for N- and C-terminal arm becoming ordered upon DNA binding.

Animals↗
PubMed2002

Calculation of protein ionization equilibria with conformational sampling: pK(a) of a model leucine zipper, GCN4 and barnase.

The use of conformational ensembles provided by nuclear magnetic resonance (NMR) experiments or generated by molecular dynamics (MD) simulations has been regarded as a useful approach to account for protein motions in the context of pK(a) calculations, yet the idea has been tested occasionally. This is the first report of systematic comparison of pK(a) estimates computed from long multiple MD simulations and NMR ensembles. As model systems, a synthetic leucine zipper, the naturally occurring coiled coil GCN4, and barnase were used. A variety of conformational averaging and titration curve-averaging techniques, or combination thereof, was adopted and/or modified to investigate the effect of extensive global conformational sampling on the accuracy of pK(a) calculations. Clustering of coordinates is proposed as an approach to reduce the vast diversity of MD ensembles to a few structures representative of the average electrostatic properties of the system in solution. Remarkable improvement of the accuracy of pK(a) predictions was achieved by the use of multiple MD simulations. By using multiple trajectories the absolute error in pK(a) predictions for the model leucine zipper was reduced to as low as approximately 0.25 pK(a) units. The validity, advantages, and limitations of explicit conformational sampling by MD, compared with the use of an average structure and a high internal protein dielectric value as means to improve the accuracy of pK(a) calculations, are discussed.

Bacterial Proteins↗
PubMed2000

Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach.

Farnesyltransferase (FT) inhibitors can suppress tumor cell proliferation without substantially interfering with normal cell growth, thus holding promise for cancer treatment. A structure-based approach to the design of improved FT inhibitors relies on knowledge of the conformational flexibility of the zinc-containing active site of FT. Although several X-ray structures of FT have been reported, detailed information regarding the active site conformational flexibility of the enzyme is still not available. Molecular dynamics (MD) simulations of FT can offer the requisite information, but have not been applied due to a lack of effective methods for simulating the four-ligand coordination of zinc in proteins. Here, we report in detail the problems that occurred in the conventional MD simulations of the zinc-bound FT and a solution to these problems by employing a simple method that uses cationic dummy atoms to impose orientational requirement for zinc ligands. A successful 1.0 ns (1.0 fs time step) MD simulation of zinc-bound FT suggests that nine conserved residues (Asn127alpha, Gln162alpha, Asn165alpha, Gln195alpha, His248beta, Lys294beta, Leu295beta, Lys353beta, and Ser357beta) in the active site of mammalian FT are relatively mobile. Some of these residues might be involved in the ligand-induced active site conformational rearrangement upon binding and deserve attention in screening and design of improved FT inhibitors for cancer chemotherapy.

Alkyl and Aryl Transferases↗
PubMed2004

Phase diagram of silica from computer simulation.

We evaluate the phase diagram of the "BKS" potential [Phys. Rev. Lett. 64, 1955 (1990)]], a model of silica widely used in molecular dynamics (MD) simulations. We conduct MD simulations of the liquid, and three crystals ( beta -quartz, coesite, and stishovite) over wide ranges of temperature and density, and evaluate the total Gibbs free energy of each phase. The phase boundaries are determined by the intersection of these free energy surfaces. Not unexpectedly for a classical pair potential, our results reveal quantitative discrepancies between the locations of the BKS and real silica phase boundaries. At the same time, we find that the topology of the real phase diagram is reproduced, confirming that the BKS model provides a satisfactory qualitative description of a silicalike material. We also compare the phase boundaries with the locations of liquid-state thermodynamic anomalies identified in previous studies of the BKS model.

Journal Article↗
PubMed2006

Anthramycin-DNA binding explored by molecular simulations.

The anticancer drug anthramycin inhibits replication and transcription processes by covalently binding to DNA. Here, we use molecular simulations to investigate the interaction between this ligand and the dodecanucleotide d[GCCAACGTTGGC](2). We start from the X-ray structure of the adduct anthramycin-d[CCAACGTTG*G](2), in which the drug binds covalently to guanine.1 We focus on the noncovalent complexes between the oligonucleotide and the anhydro and hydroxy forms of the drug. Molecular dynamics (MD) simulations show that only the hydroxy form lies in front of the reactive center for the whole simulation ( approximately 20 ns), while the anhydro form moves inside the minor groove to the nearest base pair after approximately 10 ns. This sliding process is associated to both energetic and structural relaxations of the complex. The accuracy of our computational setup is established by performing MD simulations of the covalent adduct and of a 14-mer complexed with anhydro-anthramycin. The MD simulations are complemented by hybrid Car-Parrinello quantum mechanics/molecular mechanics (QM/MM) simulations. These show that in the noncovalent complexes the electric field due to DNA polarizes the hydroxy and, even more, the anhydro form of the drug as to favor a nucleophilic attack by the alkylating guanine. This suggests that the binding process may be characterized by a multistep pathway, catalyzed by the electric field of DNA.

Anthramycin↗
PubMed2002

Structure and thermodynamics of alpha-, beta-, and gamma-cyclodextrin dimers. Molecular dynamics studies of the solvent effect and free binding energies.

The alpha-, beta-, and gamma-cyclodextrin (CyDs) dimers were studied by molecular dynamics (MD) simulations in water as an explicit solvent. The relative stability of dimers and the involved molecular interactions were determined. Three possible starting orientations were considered for the dimers: head-to-head, head-to-tail, and tail-to-tail. MD simulations were performed over a period of 5 ns to ensure the stability of the system for both the CyD dimers and monomers. The MM-PBSA methodology was used to obtain the free binding energy of the dimers and to determine the most stable arrangement for each solvated CyD. In a vacuum, MD simulations provided the head-to-head orientation as the most stable orientation for the three CyDs, while in aqueous solution the, the head-to-tail orientation was found to be the most stable for the alpha-CyD dimer and the tail-to-tail orientation the most stable for the beta- and gamma-CyD dimers.

Journal Article↗
PubMed2003

Molecular dynamics simulation of human immunodeficiency virus protein U (Vpu) in lipid/water Langmuir monolayer.

Virus protein U (Vpu) is an accessory membrane protein encoded by human immunodeficiency virus type 1 (HIV-1). Various NMR and CD studies have shown that the transmembrane domain of Vpu has a helical conformation and that the cytoplasmic domain adopts the helix-loop-helix-turn motif. This 3.5-ns molecular dynamics (MD) simulation of Vpu in a lipid/membrane environment has fully reproduced these structural characteristics. Membrane propensities of two amphipathic helices in the cytoplasmic domain are further compared here to understand better their complicated orientational behavior known from experiment. This study first reveals that the highly conserved loop region in the cytoplasmic domain can be closely associated with the membrane surface. It is known from the simulation that Vpu is associated with 34 lipids in this Langmuir monolayer. The lipids that are located between the Vpu transmembrane helix and the first helix in the cytoplasmic domain are pushed up by Vpu. These elevated lipids have increased P-N tilt angles for the head groups but unchanged acyl-chain tilt angles compared with lipids that do not interact with Vpu. This study verifies the significance of applying MD simulation in refining protein structure and revealing detailed protein-lipid interaction in membrane/water environment. Figure XZ view of a snapshot of Vpu/DLGPC/water system after 3.5 ns NP(N)gamma T MD simulation. Coloring scheme: Vpu, red; C, green; H, pink; N, blue; O, orange; P, magenta; water, light blue

Algorithms↗
PubMed2001

The combination of molecular dynamics with crystallography for elucidating protein-ligand interactions: a case study involving peanut lectin complexes with T-antigen and lactose.

Peanut lectin binds T-antigen [Galbeta(1-3)GalNAc] with an order of magnitude higher affinity than it binds the disaccharide lactose. The crystal structures of the two complexes indicate that the higher affinity for T-antigen is generated by two water bridges involving the acetamido group. Fresh calorimetric measurements on the two complexes have been carried out in the temperature range 280-313 K. Four sets of nanosecond molecular-dynamics (MD) simulations, two at 293 K and the other two at 313 K, were performed on each of the two complexes. At each temperature, two somewhat different protocols were used to hydrate the complex in the two runs. Two MD runs under slightly different conditions for each complex served to assess the reliability of the approach for exploring protein-ligand interactions. Enthalpies based on static calculations and on MD simulations favour complexation involving T-antigen. The simulations also brought to light ensembles of direct and water-mediated protein-sugar interactions in both the cases. These ensembles provide a qualitative explanation for the temperature dependence of the thermodynamic parameters of peanut lectin-T-antigen interaction and for the results of one of the two mutational studies on the lectin. They also support the earlier conclusion that the increased affinity of peanut lectin for T-antigen compared with that for lactose is primarily caused by additional water bridges involving the acetamido group. The calculations provide a rationale for the observed sugar-binding affinity of one of the two available mutants. Detailed examination of the calculations point to the need for exercising caution in interpreting results of MD simulations: while long simulations are not possible owing to computational reasons, it is desirable to carry out several short simulations with somewhat different initial conditions.

Anti-Bacterial Agents↗
PubMed2006

New force field for calcium binding sites in annexin-membrane complexes.

For accurate classical molecular dynamics (MD) simulations of the calcium mediated bound complexes of annexin and membrane we have developed new force-field parameters correctly describing the interaction of the Ca ion with its environment. We have used quantum chemical calculations to investigate the potential energy surface experienced by the Ca ion within the three different binding sites found in domain 1 of annexin V (ANX V/1). Based on these calculations we were able to quantify the charge polarization of atoms within the binding sites, and to determine the geometry and force constants of harmonic restraints between the Ca ion and its coordinating oxygen atoms. Harmonic restraints were introduced to compensate for the deviations between the quantum mechanical potential energy surface and that of the classical force field. Our analysis has shown that using the refined force field for the Ca binding sites enables long-time MD simulations that conserve the initial structure of ANX V/1 significantly better than MD simulations using the standard force field.

Annexin A5↗
PubMed2005

Influence of DPH on the structure and dynamics of a DPPC bilayer.

We have conducted extensive molecular dynamics (MD) simulations together with differential scanning calorimetry (DSC) and nuclear magnetic resonance (NMR) experiments to quantify the influence of free 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescent probes on the structure and dynamics of a dipalmitoylphosphatidylcholine bilayer. Atomistic MD simulations show that in the membrane-water interface the influence of DPH is minor, whereas in the acyl-chain region DPH gives rise to major perturbations. In the latter case, DPH is found to influence a wide range of membrane properties, such as the packing and ordering of hydrocarbon tails and the lateral diffusion of lipid molecules. The effects are prominent but of local nature, i.e., the changes observed in the properties of lipid molecules are significant in the vicinity of DPH, but reduce rapidly as the distance from the probe increases. Long-range perturbations due to DPH are hence not expected. Detailed DSC and (2)H NMR measurements support this view. DSC shows only subtle perturbation to the cooperative behavior of the membrane system in the presence of DPH, and (2)H NMR shows that DPH gives rise to a slight increase in the lipid chain order, in agreement with MD simulations. Potential effects of other probes such as pyrene are briefly discussed.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

Molecular dynamics and thermodynamics of protein-RNA interactions: mutation of a conserved aromatic residue modifies stacking interactions and structural adaptation in the U1A-stem loop 2 RNA complex.

Molecular dynamics (MD) simulations and free energy component analysis have been performed to evaluate the molecular origins of the 5.5 kcal/mol destabilization of the complex formed between the N-terminal RNP domain of U1A and stem loop 2 of U1 snRNA upon mutation of a conserved aromatic residue, Phe56, to Ala. MD simulations, including counterions and water, have been carried out on the wild type and Phe56Ala peptide-stem loop 2 RNA complexes, the free wild type and Phe56Ala peptides, and the free stem loop 2 RNA. The MD structure of the Phe56Ala-stem loop 2 complex is similar to that of the wild type complex except the stacking interaction between Phe56 and A6 of stem loop 2 is absent and loop 3 of the peptide is more dynamic. However, the MD simulations predict large changes in the structure and dynamics of helix C and increased dynamic range of loop 3 for the free Phe56Ala peptide compared to the wild type peptide. Since helix C and loop 3 are highly variable regions of RNP domains, this indicates that a significant contribution to the reduced affinity of the Phe56Ala peptide for RNA results from cooperation between highly conserved and highly variable regions of the RNP domain of U1A. Surprisingly, these structural effects, which are manifested as cooperative free energy changes, occur in the free peptide, rather than in the complex, and are revealed only by study of both the initial and final states of the complexation process. Free energy component analysis correctly accounts for the destabilization of the Phe56Ala-stem loop 2 complex, and indicates that approximately 80% of the destabilization is due to the loss of the stacking interaction and approximately 20% is due to differences in U1A adaptation.

Mutation↗
PubMed2006

Molecular dynamic simulations of the N-terminal receiver domain of NtrC reveal intrinsic conformational flexibility in the inactive state.

The N-terminal receiver domain of NtrC is the molecular switch in the two-component signal transduction. It is the first protein where structures of both the active (phosphyroylated) and inactive (unphosphyroylated) states are determined experimentally. Phosphorylation of the NtrC at the active site induces large structural change. NMR experiments suggested that the wild type unphosphorylated NtrC adopts both the active and the inactive conformations and the phosphorylation stabilizes the active conformations. We applied free (unconstrained) molecular dynamic (MD) simulation to examine the intrinsic flexibilities and stabilities of the NtrC receiver domain in both the active and inactive conformations. Molecular dynamic simulations showed that the inactive state of NtrC receiver domain is more flexible than the active state. There were large movements in helix 4 and loop beta3-alpha3 which coincide with major structural differences between the inactive and active states. We observed large root-mean-square deviations from the initial starting structure and the large root-mean-square fluctuations during MD simulation for the inactive state. We then investigated the activation pathway with Targeted MD simulation. We show that the intrinsic flexibility in the loop beta3-alpha3 plays an important role in triggering the conformational change. Phosphorylation at the active site may serve to stabilize the conformational change. These results together suggest that the unphosphorylated NtrC receiver domain could be involved in a conformational equilibrium between two different states.

Binding Sites↗