Assisted Model Building With Energy Refinement Research Articles

Synthesis, Characterization of a New Polyacrylic Acid Superabsorbent, Some Heavy Metal Ion Sorption, the Adsorption Isotherms, and Quantum Chemical Investigation.

Poly(acrylic acid/Kryptofix 23-Dimethacrylate) superabsorbent polymer [P (AA/Kry23-DM) SAP] was synthesized by solution polymerization to remove Co, Ni, Cu, Cd, Mn, Zn, Pb, Cr, and Fe ions in water and improve the quality of the water. Kry23-DM cross-linker (1,4,7,13,16-Pentaoxa-10,19 diazo cyclohexene icosane di methacrylate) was synthesized using Kry23 and methacryloyl chloride. The characterization of the molecules was done by FTIR, TGA, DSC, and SEM techniques. The effects of parameters such as pH, concentration, and the metal ion interaction on the heavy metal ions uptaking of SAP was investigated. It was observed that P (AA/Kry23-DM) SAP has maximum water absorption, and the absorption increases with the pH increase. Adsorption rates and sorption capacity, desorption ratios, competitive sorption (qcs), and distribution coefficient (log D) of P(AA/Kry23-DM) SAP were studied as a function of time and pH with the heavy metal ion concentration. Langmuir and Freundlich isotherms of the P (AA/Kry23-DM) SAP were investigated to verify the metal uptake. Molecular mechanic (MM2), Assisted Model Building with Energy Refinement (AMBER), and optimized potentials for liquid simulations (OPLS) methods. were used in quantum chemical calculations for the conformational analysis of the cross-linker and the SAP. ΔH0f calculations of the cross-linker and the superabsorbent were made using Austin Model 1(AM1) method.

Potential target identification for breast cancer and screening of small molecule inhibitors: A bioinformatics approach

In the current study, we investigated the role of PAK1 (P21 (RAC1) Activated Kinase 1) gene in breast cancer and to this end, we performed differential gene expression analysis of PAK1 in breast cancer tissues compared to the normal adjacent tissue. We also studied its significance in protein-protein interaction (PPI) network, and analysed biological pathways, cellular processes, and role of PAK1 in different diseases. We found PAK1 to have significant role in breast cancer pathways such as integrin signaling, axonal guidance signaling, signaling by Rho family GTPases, ERK5 signaling. Additionally, it has been found as hub gene in PPI network, suggesting its possible regulatory role in breast carcinogenesis. Moreover, PAK1 had role in progression of various diseases as neoplasia, tumorigenesis, lymphatic neoplasia. Thereby, PAK1 can be used as a therapeutic target in breast cancer. Further, we put our efforts in identification of potential small molecules inhibitors against PAK1 by developing a composite virtual screening protocol involving molecular dynamics (MD) and molecular docking. The chemical library of compounds from NCI diversity sets, Pubchem and eMolecules were screened against PAK1 protein and hits which showed good binding affinity were considered for MD simulation study. Moreover, to assess binding of selected hits, MMGBSA (Molecular Mechanics-Generalized Born Surface Area) analysis was performed using AMBER (Assisted Model Building with Energy Refinement) package. MMGBSA calculations exhibited that the identified ligands showed good binding affinity with PAK1. Highlights The PAK1 has been found to be upregulated in breast cancer samples and is a potential oncogene playing role in different cellular functions and processes. The molecular docking studies revealed ligands showed good binding affinity towards PAK1 protein. The residues Glu345, Leu347, Thr406, Asp299, Asp393 and Gly350 were found to make H-bond interactions with small molecule inhibitors. The residues Ile276, Val284, Ala297, Tyr346, Leu396 and Asp407 were found to make hydrophobic interactions. The RMSD analysis confirmed stability of complexes throughout 40 ns production period. The MD simulations studies revealed the binding site flexibility, binding free energy of complexes and per-residue contribution in ligand binding. Communicated by Ramaswamy H. Sarma

High-Scalable Collaborated Parallel Framework for Large-Scale Molecular Dynamic Simulation on Tianhe-2 Supercomputer

Molecular dynamics (MD) is a computer simulation method of studying physical movements of atoms and molecules that provide detailed microscopic sampling on molecular scale. With the continuous efforts and improvements, MD simulation gained popularity in materials science, biochemistry and biophysics with various application areas and expanding data scale. Assisted Model Building with Energy Refinement (AMBER) is one of the most widely used software packages for conducting MD simulations. However, the speed of AMBER MD simulations for system with millions of atoms in microsecond scale still need to be improved. In this paper, we propose a parallel acceleration strategy for AMBER on the Tianhe-2 supercomputer. The parallel optimization of AMBER is carried out on three different levels: fine grained OpenMP parallel on a single CPU, single node CPU/MIC parallel optimization and multi-node multi-MIC collaborated parallel acceleration. By the three levels of parallel acceleration strategy above, we achieved the highest speedup of 25-33 times compared with the original program.

Augmenting High-Performance Mobile Cloud Computations for Big Data in AMBER

Big data is an inspirational area of research that involves best practices used in the industry and academia. Challenging and complex systems are the core requirements for the data collation and analysis of big data. Data analysis approaches and algorithms development are the necessary and essential components of the big data analytics. Big data and high-performance computing emergent nature help to solve complex and challenging problems. High-Performance Mobile Cloud Computing (HPMCC) technology contributes to the execution of the intensive computational application at any location independently on laptops using virtual machines. HPMCC technique enables executing computationally extreme scientific tasks on a cloud comprising laptops. Assisted Model Building with Energy Refinement (AMBER) with the force fields calculations for molecular dynamics is a computationally hungry task that requires high and computational hardware resources for execution. The core objective of the study is to deliver and provide researchers with a mobile cloud of laptops capable of doing the heavy processing. An innovative execution of AMBER with force field empirical formula using Message Passing Interface (MPI) infrastructure on HPMCC is proposed. It is homogeneous mobile cloud platform comprising a laptop and virtual machines as processors nodes along with dynamic parallelism. Some processes can be executed to distribute and run the task among the various computational nodes. This task-based and data-based parallelism is achieved in proposed solution by using a Message Passing Interface. Trace-based results and graphs will present the significance of the proposed method.

Molecular docking and molecular dynamics simulations of fumarate hydratase and its mutant H235N complexed with pyromellitic acid and citrate.

Fumarase catalyzes the reversible, stereospecific hydration/dehydration of fumarate to L-malate during the Kreb's cycle. In the crystal structure of the tetrameric fumarase, it was found that some of the active site residues S145, T147, N188 G364 and H235 had water-mediated hydrogen bonding interactions with pyromellitic acid and citrate which help to the protonation state for the conversion of fumarate to malate. When His 235 is mutated with Asn (H235N), water-mediated interactions were lost due to the shifting of active site water molecule by 0.7 Å away. Molecular dynamics (MD) simulations were also carried out by NAMD and analyzed using Assisted Model Building with Energy Refinement (AMBER) program to better understand the conformational stability and other aspects during the binding of pyromellitic acid and citrate with native and mutant FH. The role of hydrogen bonds and hydrophobic interactions was also analyzed. The present study confirms that the H235N mutation has a major effect on the catalytic activity of fumarase which is evident from the biochemical studies.

Conformation change of an isotactic poly (N-isopropylacrylamide) membrane: Molecular dynamics.

In this work, isotactic Poly (N-Isopropylacrylamide)-PNIPAM-in neat water and in electrolyte solutions is studied by means of molecular dynamics simulations. This is done for an infinitely diluted oligomer and for an assembly of several PNIPAM chains arranged into a planar membrane configuration with a core-shell morphology. We employed two different force fields, AMBER (assisted model building with energy refinement) and OPLS-AA (all atom - optimized potentials for liquid simulations) in combination with extended simple point charge water. Despite the more water insoluble character of isotactic oligomers, our results support the existence of a coil to globule transition for the isolated 30-mer. This may imply the existence of an oligomer rich phase of coil-like structures in equilibrium with a water rich phase for temperatures close but below the coil to globule transition temperature, TΘ. However, the obtained coil structure is much more compact than that corresponding to the syndiotactic chain. Our estimations of TΘ are (308±5) K and (303±5) K for AMBER and OPLS-AA, respectively. The membrane configuration allows one to include chain-chain interactions, to follow density profiles of water, polymer, and solutes, and accessing the membrane-water interface tension. Results show gradual shrinking and swelling of the membrane by switching temperature above and below TΘ, as well as the increase and decrease of the membrane-water interface tension. Finally, concentration profiles for 1M NaCl and 1M NaI electrolytes are shown, depicting a strong salting-out effect for NaCl and a much lighter effect for NaI, in good qualitative agreement with experiments.

Protein's native structure is dynamically stabilized by electronic polarization

In this paper, molecular dynamics (MD) simulations were performed for a number of benchmark proteins using both the standard assisted model building with energy refinement (AMBER) charge and the dynamically adjusted polarized protein-specific charge (DPPC) from quantum fragment calculations to provide accurate electrostatic interactions. Our result shows that proteins' dynamic structures drifted away from the native structures in simulations under standard (nonpolarizable) AMBER force field. For comparison, proteins' native structures were dynamically stable after a long time simulation under DPPC. The free energy landscape reveals that the native structure is the lowest energy conformation under DPPC, while it is not under standard AMBER charge. To further investigate the polarization effect on the stability of native structures of proteins, we restarted from some decoy structures generated from simulations using standard AMBER charges and then carried out further MD simulation using DPPC to refine those structures. Our study shows that the native structures from these decoy structures can be mostly recovered using DPPC and that the dynamic structures with the highest population in cluster analysis are in close agreement with the corresponding native structures. The current study demonstrates the importance of electronic polarization of protein in stabilizing the native structure.

QuanPol: A full spectrum and seamless QM/MM program

The quantum chemistry polarizable force field program (QuanPol) is implemented to perform combined quantum mechanical and molecular mechanical (QM/MM) calculations with induced dipole polarizable force fields and induced surface charge continuum solvation models. The QM methods include Hartree-Fock method, density functional theory method (DFT), generalized valence bond theory method, multiconfiguration self-consistent field method, Møller-Plesset perturbation theory method, and time-dependent DFT method. The induced dipoles of the MM atoms and the induced surface charges of the continuum solvation model are self-consistently and variationally determined together with the QM wavefunction. The MM force field methods can be user specified, or a standard force field such as MMFF94, Chemistry at Harvard Molecular Mechanics (CHARMM), Assisted Model Building with Energy Refinement (AMBER), and Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA). Analytic gradients for all of these methods are implemented so geometry optimization and molecular dynamics (MD) simulation can be performed. MD free energy perturbation and umbrella sampling methods are also implemented.

Molecular Dynamics Simulation of Tri-n-butyl-Phosphate Liquid: A Force Field Comparative Study

Molecular dynamics (MD) simulations were conducted to compare the performance of four force fields in predicting thermophysical properties of tri-n-butyl-phosphate (TBP) in the liquid phase. The intramolecular force parameters used were from the Assisted Model Building with Energy Refinement (AMBER) force field model. The van der Waals parameters were based on either the AMBER or the Optimized Potential for Liquid Simulation (OPLS) force fields. The atomic partial charges were either assigned by performing quantum chemistry calculations or utilized previously published data, and were scaled to approximate the average experimental value of the electric dipole moment. Canonical ensemble computations based on the aforementioned parameters were performed near atmospheric pressure and temperature to obtain the electric dipole moment, mass density, and self-diffusion coefficient. In addition, the microscopic structure of the liquid was characterized via pair correlation functions between selected atoms. It has been demonstrated that the electric dipole moment can be approximated within 1% of the average experimental value by virtue of scaled atomic partial charges. The liquid mass density can be predicted within 0.5-1% of its experimentally determined value when using the corresponding charge scaling. However, in all cases, the predicted self-diffusion coefficient is significantly smaller than a commonly quoted experimental measurement; this result is qualified by the fact that the uncertainty of the experimental value was not available.

Application of molecular dynamics simulations in molecular property prediction II: diffusion coefficient.

In this work, we have evaluated how well the general assisted model building with energy refinement (AMBER) force field performs in studying the dynamic properties of liquids. Diffusion coefficients (D) have been predicted for 17 solvents, five organic compounds in aqueous solutions, four proteins in aqueous solutions, and nine organic compounds in nonaqueous solutions. An efficient sampling strategy has been proposed and tested in the calculation of the diffusion coefficients of solutes in solutions. There are two major findings of this study. First of all, the diffusion coefficients of organic solutes in aqueous solution can be well predicted: the average unsigned errors and the root mean square errors are 0.137 and 0.171 × 10(-5) cm(-2) s(-1), respectively. Second, although the absolute values of D cannot be predicted, good correlations have been achieved for eight organic solvents with experimental data (R(2) = 0.784), four proteins in aqueous solutions (R(2) = 0.996), and nine organic compounds in nonaqueous solutions (R(2) = 0.834). The temperature dependent behaviors of three solvents, namely, TIP3P water, dimethyl sulfoxide, and cyclohexane have been studied. The major molecular dynamics (MD) settings, such as the sizes of simulation boxes and with/without wrapping the coordinates of MD snapshots into the primary simulation boxes have been explored. We have concluded that our sampling strategy that averaging the mean square displacement collected in multiple short-MD simulations is efficient in predicting diffusion coefficients of solutes at infinite dilution.

Relative stability of the open and closed conformations of the active site loop of streptavidin.

The eight-residue surface loop, 45-52 (Ser, Ala, Val, Gly, Asn, Ala, Glu, Ser), of the homotetrameric protein streptavidin has a "closed" conformation in the streptavidin-biotin complex, where the corresponding binding affinity is one of the strongest found in nature (ΔG ∼ -18 kcal∕mol). However, in most of the crystal structures of apo (unbound) streptavidin, the loop conformation is "open" and typically exhibits partial disorder and high B-factors. Thus, it is plausible to assume that the loop structure is changed from open to closed upon binding of biotin, and the corresponding difference in free energy, ΔF = F(open) - F(closed) in the unbound protein, should therefore be considered in the total absolute free energy of binding. ΔF (which has generally been neglected) is calculated here using our "hypothetical scanning molecular-dynamics" (HSMD) method. We use a protein model in which only the atoms closest to the loop are considered (the "template") and they are fixed in the x-ray coordinates of the free protein; the x-ray conformation of the closed loop is attached to the same (unbound) template and both systems are capped with the same sphere of TIP3P water. Using the force field of the assisted model building with energy refinement (AMBER), we carry out two separate MD simulations (at temperature T = 300 K), starting from the open and closed conformations, where only the atoms of the loop and water are allowed to move (the template-water and template-loop interactions are considered). The absolute F(open) and F(closed) (of loop + water) are calculated from these trajectories, where the loop and water contributions are obtained by HSMD and a thermodynamic integration (TI) process, respectively. The combined HSMD-TI procedure leads to total (loop + water) ΔF = -27.1 ± 2.0 kcal∕mol, where the entropy TΔS constitutes 34% of ΔF, meaning that the effect of S is significant and should not be ignored. Also, ΔS is positive, in accord with the high flexibility of the open loop observed in crystal structures, while the energy ΔE is unexpectedly negative, thus also adding to the stability of the open loop. The loop and the 250 capped water molecules are the largest system studied thus far, which constitutes a test for the efficiency of HSMD-TI; this efficiency and technical issues related to the implementation of the method are also discussed. Finally, the result for ΔF is a prediction that will be considered in the calculation of the absolute free energy of binding of biotin to streptavidin, which constitutes our next project.

A novel sequence variation in the transactivation regulating domain of the human androgen receptor

To study a novel sequence variation within the androgen receptors' N-terminal CAG repeat region and possible resulting consequences for the receptors' three-dimensional (3D) protein structure. Controlled clinical study. University research and andrology clinic. Twenty-one adult infertile men. Ultraviolet laser-assisted microdissection (PALM, Microlaser Technology AG, Bernried, Germany), cloning into pGEM-T vector (Promega, Madison, WI), automated sequencing (Gene Scan 3.7 ABI Prim, Applied Biosystems, Foster City, CA), and Assisted Model Building with Energy Refinement (AMBER). Determination of the sequence of the CAG repeat of the androgen receptor gene and analysis of the 3D protein structure. In one hypergonadotropic azoospermic patient with Sertoli-cell-only syndrome, we found a punctual sequence variation of 212A-->G in the CAG repeat resulting in a glutamine-arginine substitution, which leads to a moderate conformational change of the alpha-helix from 34 A in length and 16 A in diameter (without mutation) to a slightly longer helix (43 A) with a smaller diameter (15 A). Whether the novel 212A-->G exchange in the CAG repeat leading to a glutamine-->arginine substitution and a change in alpha-helix structure may causally be related to the Sertoli-cell-only phenotype of the patient remains to be elucidated.

Direct calculation of the binding free energies of FKBP ligands

Direct calculations of the absolute free energies of binding for eight ligands to FKBP protein were performed using the Fujitsu BioServer massively parallel computer. Using the latest version of the general assisted model building with energy refinement (AMBER) force field for ligand model parameters and the Bennett acceptance ratio for computing free-energy differences, we obtained an excellent linear fit between the calculated and experimental binding free energies. The rms error from a linear fit is 0.4 kcal/mol for eight ligand complexes. In comparison with a previous study of the binding energies of these same eight ligand complexes, these results suggest that the use of improved model parameters can lead to more predictive binding estimates, and that these estimates can be obtained with significantly less computer time than previously thought. These findings make such direct methods more attractive for use in rational drug design.

Atomic properties of amino acids: computed atom types as a guide for future force-field design.

The quantum chemical topology (QCT) is able to propose atom types by direct computation rather than by chemical intuition. In previous work, molecular electron densities of 20 amino acids and smaller derived molecules were partitioned into a set of 760 topological atoms. Each atom was characterised by seven atomic properties and subjected to cluster analysis element by element, that is, C, H, O, N, and S. From the respective dendrograms, 21 carbon atom types were distinguished, 7 hydrogen, 2 nitrogen, 6 oxygen, and 6 sulfur atom types. Herein, we contrast the QCT atom types with those of the assisted model building with energy refinement (AMBER) force field. We conclude that in spite of fair agreement between QCT and AMBER atom types, the latter are sometimes underdifferentiated and sometimes overdifferentiated. In summary, we suggest that QCT is a useful guide in designing new force fields or improving existing ones. The computational origin of QCT atom types makes their determination unbiased compared to atom type determination by chemical intuition and a priori assumptions. We provide a list of specific recommendations.

Molecular dynamics exposes alpha-helices in myelin basic protein.

Molecular dynamics simulations of models of unmodified and deiminated MBP (myelin basic protein) have been performed on solvated structures with added counterions, for 10 ns using AMBER (assisted model building with energy refinement). The protein structures became extended, and a considerable number of alpha-helical segments formed spontaneously. The degree of molecular extension was greater in the deiminated species, and the alpha-helices were more transient. These structural disruptions may be operative in vivo during multiple sclerosis.

Large Scale Simulation of Protein Mechanics and Function

The chapter illustrates the state of art in large-scale biomolecular modeling. Such modeling has become feasible only through parallel computing utilizing hundreds and soon thousands of processors. Fortunately, the necessary computers are available to many researchers and the needed new generation of molecular dynamics and molecular visualization programs has been developed and these resources are widely shared. Harnessing them effectively requires great effort, to which purpose the authors' group has developed the molecular dynamics program Not (just) Another Molecular Dynamics program (NAMD). For the graphical analysis of the ensuing gigabytes and terabytes of data the group has developed the program Visual Molecular Dynamics (VMD). These programs are widely used today since the increasing availability of protein structures has led to most biomedical researchers using structural information for the design and analysis of their experiments. The chapter describes NAMD and VMD and illustrates three exemplary simulations of large-scale systems that are presently the subject of intense research. The functions of all three proteins investigated are mainly mechanical. NAMD is primarily designed to work with Chemistry at HARvard Molecular Mechanics (CHARMM) force field parameters. Input files for NAMD can be generated using CHARMM, X-PLOR, or VMD. NAMD has also been extended to read Assisted Model Building with Energy Refinement (AMBER) and GROningen MAchine for Chemical Simulations (GROMACS) input file formats. NAMD running on 768 processors has enabled a record-breaking two million atom 5 ns simulation of the ribosome using an AMBER force field. To relate the observed mechanics to the architecture of proteins is the domain of so-called steered molecular dynamics simulations, contributing to the founding of the new field of mechanobiology, which studies the role of forces in cellular processes.

PAPQMD/AM1 Parametrization of the bonded term of aromatic biomolecules

AbstractThe suitability of the PAPQMD/AM1 (Program for Approximate Parametrization from Quantum Mechanical Data/based on AM1 calculations) strategy to provide force‐field parameters for large heteroaromatic compounds was studied. For this purpose, PAPQMD/AMI stretching and bending parameters for adenine, cytosine, thymine, guanine, and uracil were computed and compared with experimentally derived force‐field parameters. Furthermore, equilibrium geometries and vibrational spectra for the five nucleic acid bases obtained from molecular mechanical calculations using both PAPQMD/AM1 and AMBER (Assisted Model Building with Energy Refinement) All Atoms force fields were compared with the available experimental data. © 1994 John Wiley & Sons, Inc.

The different influences of ether and ester phospholipids on the conformation of gramicidin A. A molecular modelling study

With AMBER (assisted model building with energy refinement) molecular modelling techniques, the interactions between lipids which differ in the type of chain linkage (e.g., ether or ester) and gramicidin were approximated. It was found, theoretically, that replacement of the ester function in dipalmitoylphosphatidylcholine (DPPC) by an ether moiety induces a shift in the rotameric distribution of the Trp-15 side-chain in gramicidin A. Concomitantly, the channel entrance is contracted by approx. 0.4Å. The perturbation can be related to the strong hydrogen-bond formed between the lipid carbonyl group and the indole proton of the Trp-15 residue of gramicidin. In the ether lipid-gramicidin assembly a weaker H-bond is formed between Trp-15 and the phosphate moiety. To obtain a first indication of the influence of the strength of this H-bond on gramicidin A, a preliminary experimental study was set up. The transport properties of gramicidin A were studied using efflux measureents through vesicle walls containing ether and ester lipids, respectively. A change in the permeability of gramicidin A was found when ether lipids were added to a bilayer composed of the ester lipid dioleoylphosphatidylcholine (DOPC).

Effect of calcium (II) and magnesium (II) ions on the 18-23 gamma-carboxyglutamic acid containing cyclic peptide loop of bovine prothrombin. An AMBER molecular mechanics study.

The effect of calcium (II) and magnesium (II) ions on the conformation of the 18-23 cyclic peptide loop of bovine prothrombin are investigated by the molecular mechanics program AMBER (Assisted Model Building with Energy Refinement). The work is an extension of an earlier paper (Eastman et al., Int. J. Peptide Protein Res. 27, 1986, 530-553) that employed the program ECEPP (Empirical Conformational Energy Program for Peptides). In the absence of either metal ion, or in the presence of either one Ca(II) or one Mg(II) ion, the lowest-energy forms found by AMBER have the Gla21-Pro22 peptide bond in a trans conformation. In the presence of two Ca(II) or Mg(II) ions, the loop form of lowest energy is decidedly cis. The coordination about the Ca(II) and Mg(II) ions is different in both the single and double metal cases. In addition, the peptide chains that emerge from the loop are oriented parallel to each other in the lowest-energy complex with two Ca(II) ions, but are not parallel in the lowest-energy complex with two Mg(II) ions.