羟基化树状大分子与布洛芬相互作用的分子模拟研究

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。     

Ordinary differential equations of molecular dynamics

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.     

Effects of different solvents on the conformations of apoptotic cytochrome c: Structural insights from molecular dynamics simulation

Cytochrome c (cyt-c) upon binding with cardiolipin acquires peroxidase activity and is strictly connected to the pathogenesis of many human diseases including neurodegenerative and cardiovascular diseases. Interaction of cyt-c with cardiolipin mimics partial unfolding/conformational changes of cyt-c in different solvent environments. Dynamic pictures of these conformational changes of cyt-c are crucial in understanding their physiological roles in mitochondrial functions. Therefore, atomistic molecular dynamics (MD) simulations have been carried out to investigate the effect of different solvents (water, urea/water, MeOH and DMSO) on the structure and conformations of apoptotic cyt-c (Fe³⁺). Our study demonstrates that the structural changes in the protein are solvent dependent. The structural differences are observed majorly on the β-sheets and α-helical conformations and the degree of their perturbation are specific to the solvent. Although a complete loss of β-sheets (0%) is observed in MeOH and DMSO, by contrast, well preserved β-sheets (3.84%) are observed in water and urea/water. A significant decrease in the α-helical contents is observed in MeOH (41.34%) and water (42.46%), a negligible alteration in DMSO (44.25%) and well preserved α-helical (45.19%) contents in urea/water. The distances between the residues critical for electron transfer are decreased considerably for DMSO. Further, the reduction in residue flexibility and the conformational space indicate that the collective motions of cyt-c are reduced when compared to other cosolvents. Essential dynamics analysis implies that the overall motions of cyt-c in water, MeOH and urea/water are involved in three to four eigenvectors and in first eigenvector in DMSO. Overall, we believe that MD simulations of cyt-c in different solvents can provide a detailed microscopic understanding of the physiological roles, electron transport and peroxidase function in the early events of apoptosis which are hard to probe experiments.     

多体问题在GPU上实现的讨论

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。     

Highly accelerated simulations of glassy dynamics using GPUs: Caveats on limited floating-point precision

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.     

Effect of temperature on the structure and hydration layer of TATA-box DNA: A molecular dynamics simulation study

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 B_I and B_II 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.     

Conformational flexibility decreased due to Y67F and F82H mutations in cytochrome c: Molecular dynamics simulation studies

Cytochrome c (cyt c), a mitochondrial protein, has dual functions in controlling both cellular energetic metabolism and apoptosis (programmed cell death). During apoptosis, cyt c (Fe³⁺) released into the cytosol initiates caspase activation leading to apoptosis. Since, X-ray crystallography gives only the static structure, we report here the dynamic behavior of holo and apo wild type (WT), Y67F and F82H mutant cyt c's (Fe³⁺) in their apoptotic states. Four nanosecond MD simulations were run for holo WT, Y67F and F82H cyt c's with and without FeS (Met-80) bond and also for apo WT and mutated cyt c's (Y67F and F82H) in water using GROMOS96 force field. Mutations of Y67F and F82H resulted in the decrease of backbone and Cα RMSDs, and radii of gyration (backbone and protein) in both the holo and apo forms. MD and ED results revealed that the flexibility of mutated holo cyt c's decreased perhaps affecting their ability to take part in mitochondrial electron/proton transfer process. Without FeS bond, the backbone and Cα RMSD increased in holo cyt c's perhaps resulting in enhanced peroxidase activity. ED revealed that four to six eigenvectors involved in over all motions of holo cyt c's without FeS bond, and six to eight eigenvectors in apo cyt c's in comparison to three to four eigenvectors for holo cyt c's with FeS bond.     

Why do the outer membrane proteins OmpF from E. coli and OprP from P. aeruginosa prefer trimers? Simulation studies

Porins are water-filled protein channels across the outer membrane of gram-negative bacteria. They facilitate the uptake of nutrients and essential ions. Solutes are filtered by a constriction loop L3 at the mid of a pore. Porins are heat-stable and resistant to toxic agents and detergents. Most porins are trimer, but no clear explanation why trimeric form is preferable. In this work, we thus studied effects of oligomerization on porin structure and function in microscopic detail. A well-studied OmpF (general porin from Escherichia coli) and well-characterised OprP (phosphate-specific pore from Pseudomonas aeruginosa) are used as samples from 2 types of porins found in gram-negative bacteria. MD simulations of trimeric and monomeric pores in pure water and 1 M NaCl solution were performed. With a salt solution, the external electric field was applied to mimic a transmembrane potential. Expectedly, OprP is more stable than OmpF. Interestingly, being a monomer turns OmpF into an anion-selective pore. The dislocation of D113’s side chain on L3 in OmpF causes the disruption of cation pathway resulting in the reduction of cation influx. In contrast, OprP's structure and function are less dependent on oligomeric states. Both monomeric and trimeric OprP can maintain their anion selectivity. Our findings suggest that trimerization is crucial for both structure and function of general porin OmpF, whereas being trimer in substrate-specific channel OprP supports a pore function.