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1.
l-Alanine dehydrogenase from Mycobacterium tuberculosis (l-MtAlaDH) catalyzes the NADH-dependent interconversion of l-alanine and pyruvate, and it is considered to be a potential target for the treatment of tuberculosis. The experiment has verified that amino acid replacement of the conserved active-site residues which have strong stability and no great changes in biological evolutionary process, such as His96 and Asp270, could lead to inactive mutants [Ågren et al., J. Mol. Biol. 377 (2008) 1161–1173]. However, the role of these conserved residues in catalytic reaction still remains unclear. Based on the crystal structures, a series of mutant structures were constructed to investigate the role of the conserved residues in enzymatic reaction by using molecular dynamics simulations. The results show that whatever the conserved residues were mutated, the protein can still convert its conformation from open state to closed state as long as NADH is present in active site. Asp270 maintains the stability of nicotinamide ring and ribose of NADH through hydrogen bond interactions, and His96 is helpful to convert the protein conformation by interactions with Gln271, whereas, they would lead to the structural rearrangement in active site and lose the catalytic activity when they were mutated. Additionally, we deduce that Met301 plays a major role in catalytic reaction due to fixing the nicotinamide ring of NADH to prevent its rotation, and we propose that Met301 would be mutated to the hydrophobic residue with large steric hindrance in side chain to test the activity of the protein in future experiment. 相似文献
2.
采用分子对接和分子动力学(MD)的模拟方法研究了第四代羟基为末端基团的树状大分子(PAMAM-G4-OH)与布洛芬的相互作用机理并对形成的复合物稳定性进行研究,结果发现:布洛芬插入PAMAM-G4-OH树状大分子空穴,羧基基团靠近核心;对接过程中分子间的范德华力和分子间的氢键贡献很大;将复合物体系进行2000 ps的MD模拟,发现前1000 ps体系的势能、总能量和RMSD值持续下降趋于平衡,最后分别在-1639 kcal/mol～-1701 kcal/mol,-457.009 kcal/mol～-475.809 kcal/mol,0.487A～0.607A范围内波动:复合物的结构起先较松散,经过2000 ps的模拟后逐渐紧凑。结论:树状大分子(PAMAM-G4-OH)与布洛芬主要作用力主为静电力,该静电力主要由布洛芬的羧基去质子化后形成的负电离子和树状大分子内部碱性的叔胺离子产生的;经过2000 ps的分子动力学模拟后,该体系达到了稳定状态。 相似文献
3.
The ordinary differential equations of Newtonian dynamics are used in atomic simulations with the method of molecular dynamics. The basic issues are surveyed and standard algorithms are described. Several algorithmic variants are discussed. Some advanced ideas relating to parallel computation are considered. 相似文献
4.
多体问题(N-body)是力学的基本问题之一,研究N个质点互相作用的运动规律。结合分子动力学计算模拟软件LAMMPS和天体多体物理模拟软件Gadget-2这两个有广泛应用的多体并行计算软件,分析其基本算法和实现,讨论这两个有代表性的并行计算软件在GPU等加速部件上移植的基本思路。 相似文献
5.
Currently, Vorapaxar is the only recently FDA-approved antiplatelet drug targeting Protease-activated receptor 1 (PAR1). However, a novel antagonist, F16357, has been shown to prevent painful bladder syndrome, also known as interstitial cystitis (IC). Unfortunately, there is no high resolution structure of the F16357-receptor complex, hindering its optimization as a therapeutic agent. In this study, we used docking and molecular dynamic (MD) simulations to investigate the detailed interactions between F16357 and PAR1 at a molecular level. The recently solved crystal structure of human PAR1 complexed with Vorapaxar was used in our docking of F16357 into the binding pocket of the receptor. To enhance binding pose selection, F16357 was docked first without constraints and then with a positional constraint to invert its orientation to become similar to that of Vorapaxar. The three systems, with crystal Vorapaxar, F16357 and an inverted F16357, were subjected to 3.0 μs MD simulations. The MM-GBSA binding energy analysis showed that F16357 binds more strongly in a pose obtained from an unrestrained docking than in the inverted pose from a restrained docking; and Vorapaxar binds more strongly than F17357. This ordering is consistent with the experimental pIC50 values. Our structural data showed subtle changes in the binding pose between Vorapaxar and F16357. Transmembrane helices 1, 2, 5, and 7 were most significantly affected; most notably a large kink at F2795.47 in TM helix 5 of the Vorapaxar complex was completely absent in the F16357 complex. The results of this study facilitate the future development of other therapeutic PAR1 antagonists. 相似文献
6.
The GAF domain located in the N-terminal motifs of CodY (N-CodY) is responsible for increasing the affinity of CodY to its target sites on DNA by its interaction with the branched chain amino acids (BCAAs) involving isoleucine, leucine and valine. The study of the interaction of GAF domain with isoleucine gains much attention in recent years, but the mechanism of isoleucine release still remains unclear. In this paper, a conventional molecular dynamics (MD) and force probe molecular dynamics (FPMD) simulations have been performed with the aim to understand how the isoleucine ligand escapes from the GAF domain of N-CodY from Bacillus subtilis. The MD results reveal that the ligand release is a gradual process, which is accompanied by the movement of the loop between β3 and β4. During the periods of ligand escaping from the bottom to the top of binding pocket, isoleucine forms hydrogen bonds one after another with series of residues, such as ARG61, THR96, PHE98, VAL100, GLU101 and ASN102, under the mediation of hydrophobic contacts. The FPMD results show that the easiest way to pull ligand out of the cavity is along x direction (i.e. the direction is opposite to MET62). 相似文献
7.
Dihydroxylammonium 5,5′-bistetrazole-1,1′-diolate (TKX-50) is a newly synthesized energetic material with excellent comprehensive properties. Cyclotrimethylenetrinitramine (RDX) is currently one of the most widely used energetic materials in the world. TKX-50 and RDX supercell models and TKX-50/RDX cocrystal model were constructed based on their crystal cell parameters and the formation mechanism of cocrystal, respectively, then they were simulated by molecular dynamics (MD) simulations. The maximum trigger bond (NNO2) length(Lmax), binding energy (Ebind), radial distribution function (RDF), cohesive energy density(CED) and mechanical properties were simulated at different temperatures based on the simulated equilibrium structures of the models. The simulated results indicate that hydrogen bond and van der Waals force interactions exist in the cocrystal system and the hydrogen bonds are mainly derived from the hydrogen atom of TKX-50 with the oxygen or nitrogen atom of RDX. Moreover, TKX-50/RDX cocrystal structure significantly reduces the sensitivity and improves the thermodynamic stability of RDX, and it also shows better mechanical properties than pure TKX-50 and RDX, indicating that it will vastly expand the application scope of the single compound explosives. 相似文献
8.
Modern graphics processing units (GPUs) provide impressive computing resources, which can be accessed conveniently through the CUDA programming interface. We describe how GPUs can be used to considerably speed up molecular dynamics (MD) simulations for system sizes ranging up to about 1 million particles. Particular emphasis is put on the numerical long-time stability in terms of energy and momentum conservation, and caveats on limited floating-point precision are issued. Strict energy conservation over 108 MD steps is obtained by double-single emulation of the floating-point arithmetic in accuracy-critical parts of the algorithm. For the slow dynamics of a supercooled binary Lennard-Jones mixture, we demonstrate that the use of single-floating point precision may result in quantitatively and even physically wrong results. For simulations of a Lennard-Jones fluid, the described implementation shows speedup factors of up to 80 compared to a serial implementation for the CPU, and a single GPU was found to compare with a parallelised MD simulation using 64 distributed cores. 相似文献
9.
报道了三嗪类化合物与豌豆Ｄ１蛋白结合的分子模拟研究,。结果表明,三嗪类化合物主要以氢键方式与Ｄ１蛋白结合,同时亦发现,ＳＥＲ２６８域ＨＩＳ２１５是经合物与Ｄ１艇时重要的结合位点。 相似文献
10.
The present work combines molecular docking calculations, 3D-QSAR, molecular dynamics simulations and free binding energy calculations (MM/PBSA and MM/GBSA) in a set of 28 structural analogues of acyl homoserine lactones with Quorum Sensing antagonist activity. The aim of this work is to understand how ligand binds and is affected by the molecular microenvironment in the active site of the LasR receptor for pseudomonas aeruginosa. We also study the stability of the interaction to find key structural characteristics that explain the antagonist activities of this set of ligands. This information is relevant for the rational modification or design of molecules and their identification as powerful LasR modulators.The analysis of molecular docking simulations shows that the 28 analogues have a similar binding mode compared to the native ligand. The carbonyl groups belonging to the lactone ring and the amide group of the acyl chain are oriented towards the amino acids forming hydrogen bond like interactions. The difference in antagonist activity is due to location and orientation of the LasR side chains within the hydrophobic pocket in its binding site. Additionally, we carried out molecular dynamics simulations to understand the conformational changes in the ligand-receptor interaction and the stability of each complex. Results show a direct relationship among the interaction energies of the ligands and the activities as an antagonist of the LasR receptor. 相似文献
11.
Enormous efforts have been made in the past to identify novel scaffolds against the potential therapeutic target, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Fourteen different organic molecules have been crystallized to understand the structural basis of the inhibition. However, the pharmacophoric studies carried out so far, have not exploited all the structural information simultaneously to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore hypotheses from the available PfDHODH structural proteome. Among the generated hypotheses, a representative hypothesis was employed as a primary filter to list the molecules with complimentary features accountable for inhibition. Moreover, the auxiliary evaluations of the filtered molecules were accomplished via docking and drug-likeness studies. Subsequently, the stability of the protein-ligand complex was evaluated by using molecular dynamics simulations (MDs). The molecular details of binding interactions of the potential hits were compared with the highly active experimental structure (5FI8) to seek the more potent candidates that can be targeted against PfDHODH. Overall, the combination of screening and stability procedures resulted in the identification of three potent candidates. The drug-likeness of these molecules lie within the acceptable range and consequently increased the opportunities for their development to new anti-malarials. 相似文献
12.
Urea transporters (UTs) are transmembrane proteins that transport urea molecules across cell membranes and play a crucial role in urea excretion and water balance. Modeling the functional characteristics of UTs helps us understand how their structures accomplish the functions at the atomic level, and facilitates future therapeutic design targeting the UTs. This study was based on the crystal structure of Desulfovibrio vulgaris urea transporter (dvUT). To model the binding behavior of urea molecules in dvUT, we constructed a cooperative binding model. To model the substitution of urea by the urea analogue N,N′-dimethylurea (DMU) in dvUT, we calculated the occupation probability of DMU along the urea pore and the ratio of the occupation probabilities of DMU at the external (Sext) and internal (Sint) binding sites, and we established the mutual substitution rule for binding and substitution of urea and DMU. Based on these calculations and modelings, together with the use of the Monte Carlo (MC) method, we further modeled the urea flux in dvUT, equilibrium urea binding to dvUT, and the substitution of urea by DMU in the dvUT. Our modeling results are in good agreement with the existing experimental functional data. Furthermore, the modelings have discovered the microscopic process and mechanisms of those functional characteristics. The methods and the results would help our future understanding of the underlying mechanisms of the diseases associated with impaired UT functions and rational drug design for the treatment of these diseases. 相似文献
13.
Roscovitine derivatives are potent inhibitors of cyclin-dependent kinase 5 (CDK5), but they exhibit different activities, which has not been understood clearly up to now. On the other hand, the task of drug design is difficult because of the fuzzy binding mechanism. In this context, the methods of molecular docking, molecular dynamics (MD) simulation, and binding free energy analysis are applied to investigate and reveal the detailed binding mechanism of four roscovitine derivatives with CDK5. The electrostatic and van der Waals interactions of the four inhibitors with CDK5 are analyzed and discussed. The calculated binding free energies in terms of MM-PBSA method are consistent with experimental ranking of inhibitor effectiveness for the four inhibitors. The hydrogen bonds of the inhibitors with Cys83 and Lys33 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the pivotal contacts with Ile10 and Leu133 have larger contributions to the binding free energy and play critical roles in distinguishing the variant bioactivity of four inhibitors. In terms of binding mechanism of the four inhibitors with CDK5 and energy contribution of fragments of each inhibitor, two new CDK5 inhibitors are designed and have stronger inhibitory potency. 相似文献
14.
报道了三嗪类化合物与豌豆 Ｄ１ 蛋白结合的分子模拟研究。结果表明, 三嗪类化合物主要以氢键方式与 Ｄ１ 蛋白结合, 同时亦发现, Ｓ Ｅ Ｒ２６８ 或 Ｈ Ｉ Ｓ２１５ 是这类化合物与 Ｄ１ 蛋白作用时重要的结合位点 相似文献
15.
Structure-based prediction for the site of metabolism (SOM) of a compound metabolized by human cytochrome P450s (CYPs) is highly beneficial in drug discovery and development. However, the flexibility of the CYPs’ active site remains a huge challenge for accurate SOM prediction. Compared with other CYPs, the active site of CYP2A6 is relatively small and rigid. To address the impact of the flexibility of CYP2A6 active site residues on the SOM prediction for substrates, in this work, molecular dynamics (MD) simulations and molecular docking were used to predict the SOM of 96 CYP2A6 substrates. Substrates with known SOM were docked into the snapshot structures from MD simulations and the crystal structures of CYP2A6. Compared to the crystal structures, the protein structures obtained from MD simulations showed more accurate prediction for SOM. Our results indicated that the flexibility of the active site of CYP2A6 significantly affects the SOM prediction results. Further analysis for the 40 substrates with definite Km values showed that the prediction accuracy for the low Km substrates is comparable to that by ligand-based methods. 相似文献
16.
Hydrophobins are proteins of interest for numerous applications thanks to their unique conformational and surface properties and their ability to self-assemble at interfaces. Here we report fully atomistic molecular mechanics and molecular dynamics results together with circular dichroism experimental data, aimed to study the conformational properties of the hydrophobin HFBII in a fluorinated solvent in comparison with a water solution and/or at an aqueous/vacuum interface. Both the atomistic simulations and the circular dichroism data show the remarkable structural stability of HFBII at all scales in all these environments, with no significant structural change, although a small cavity is formed in the fluorinated solvent. The combination of theoretical calculations and circular dichroism data can describe in detail the protein conformation and flexibility in different solvents and/or at an interface, and constitutes a first step towards the study of their self-assembly. 相似文献
17.
Pinostrobin (PNS) is one of the important flavonoids and can be abundantly found in the rhizomes of fingerroot (Boesenbergia rotrunda) and galangal (Alpinia galangal and Alpinia officinarum), the herbal basis of Southeast Asian cooking. Similar to other flavonoids, PNS exhibits anti-oxidative, anti-inflammatory and anti-cancer properties. However, this compound has an extremely low water solubility that limits its use in pharmaceutical applications. Beta-cyclodextrin (βCD) and its derivatives, 2,6-dimethyl-βCD (2,6-DMβCD) and the three hydroxypropyl-βCDs (2-HPβCD, 6-HPβCD and 2,6-DHPβCD), have unique properties that enhance the stability and solubility of such low-soluble guest molecules. In the present study, molecular dynamics simulations were applied to investigate the dynamics and stability of PNS inclusion complexes with βCD and its derivatives (2,6-DMβCD, 2,6-DHPβCD, 2-HPβCD and 6-HPβCD). PNS was able to form complexes with βCD and all four of its derivatives by either the chromone (C-PNS) or phenyl (P-PNS) ring dipping toward the cavity. According to the molecular mechanics-generalized Born surface area binding free energy values, the stability of the different PNS/βCD complexes was ranked as 2,6-DHPβCD > 2,6-DMβCD > 2-HPβCD > 6-HPβCD > βCD. These theoretical results were in good agreement with the stability constants that had been determined by the solubility method. 相似文献
18.
DNA within the living cells experiences a diverse range of temperature, ranging from freezing condition to hot spring water. How the structure, the mechanical properties of DNA, and the solvation dynamics around DNA changes with the temperature is important to understand the functionality of DNA under those acute temperature conditions. In that notion, we have carried out molecular dynamics simulations of a DNA oligomer, containing TATA-box sequence for three different temperatures (250 K, 300 K and 350 K). We observed that the structure of the DNA, in terms of backbone torsion angles, sugar pucker, base pair parameters, and base pair step parameters, did not show any unusual properties within the studied range of temperatures, but significant structural alteration was noticed between BI and BII forms at higher temperature. As expected, the flexibility of the DNA, in terms of the torsional rigidity and the bending rigidity is highly temperature dependent, confirming that flexibility increases with increase in temperature. Additionally, the groove widths of the studied DNA showed temperature sensitivity, specifically, the major groove width decreases and the minor groove width increases, respectively, with the increase in temperature. We observed that at higher temperature, water around both the major and the minor groove of the DNA is less structured. However, the water dynamics around the minor groove of the DNA is more restricted as compared to the water around the major groove throughout the studied range of temperatures, without any anomalous behavior. 相似文献
19.
Biomolecular recognition of proteins and nucleic acids is mainly mediated by their structural features and the molecular dynamics simulations approach has been used to explore this recognition processes at the atomic level. L1-Endonuclease, an enzyme involved in L1 retrotransposition, cleaves the TA junction DNA (5′-TTTT/AA-3′) and expresses high specificity for target site recognition. The present study highlights the structural features of L1-endonuclease as well as DNA responsible for such specific recognition. Especially, the importance of βB6-B5 hairpin loop in DNA recognition has been elucidated by analyzing the dynamics of Thr192 mutated L1-endonuclease. In addition, simulations of the endonuclease complexed with DNA substrates (sequences having TA and CG junctions) revealed the specificity of L1 endonuclease towards TA junction. Molecular dynamics simulations revealed that the βB6-B5 hairpin loop protrudes well into the minor groove of DNA having TA junction and induces DNA bending such that the width of minor groove is increased. Such endonuclease induced bending of TA junction DNA sequence positions the scissile phosphodiester bond of DNA for cleavage. The innate property of minor groove widening in TA junction than in CG junction is utilized by the βB6-βB5 hairpin loop of endonuclease while recognizing the DNA sequences. The present study also highlights the role of Mg2+ cation in catalysis and attempts to explore the possible target site DNA cleavage mechanism. 相似文献
20.
The nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structure-based approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations. The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The results provide valuable information for the development of inhibitors for CHIKV. 相似文献