Unit-vector RMS (URMS) as a tool to analyze molecular dynamics trajectories

The Unit-vector RMS (URMS) is a new technique to compare protein chains and to detect similarities of chain segments. It is limited to comparison of C(alpha) chains. However, it has a number of unique features that include exceptionally weak dependence on the length of the chain and efficient detection of substructure similarities. Two molecular dynamics simulations of proteins in the neighborhood of their native states are used to test the performance of the URMS. The first simulation is of a solvated myoglobin and the second is of the protein MHC. In accord with previous studies the secondary structure elements (helices or sheets) are found to be moving relatively rigidly among flexible loops. In addition to these tests, folding trajectories of C peptides are analyzed, revealing a folding nucleus of seven amino acids.     

Extended molecular dynamics of a c-kit promoter quadruplex

The 22-mer c-kit promoter sequence folds into a parallel-stranded quadruplex with a unique structure, which has been elucidated by crystallographic and NMR methods and shows a high degree of structural conservation. We have carried out a series of extended (up to 10 μs long, ∼50 μs in total) molecular dynamics simulations to explore conformational stability and loop dynamics of this quadruplex. Unfolding no-salt simulations are consistent with a multi-pathway model of quadruplex folding and identify the single-nucleotide propeller loops as the most fragile part of the quadruplex. Thus, formation of propeller loops represents a peculiar atomistic aspect of quadruplex folding. Unbiased simulations reveal μs-scale transitions in the loops, which emphasizes the need for extended simulations in studies of quadruplex loops. We identify ion binding in the loops which may contribute to quadruplex stability. The long lateral-propeller loop is internally very stable but extensively fluctuates as a rigid entity. It creates a size-adaptable cleft between the loop and the stem, which can facilitate ligand binding. The stability gain by forming the internal network of GA base pairs and stacks of this loop may be dictating which of the many possible quadruplex topologies is observed in the ground state by this promoter quadruplex.     

The atomistic mechanism of conformational transition in adenylate kinase: a TEE-REX molecular dynamics study

We report on an atomistic molecular dynamics simulation of the complete conformational transition of Escherichia coli adenylate kinase (ADK) using the recently developed TEE-REX algorithm. Two phases characterize the transition pathway of ADK, which folds into the domains CORE and LID and the AMP binding domain AMPbd. Starting from the closed conformation, half-opening of the AMPbd precedes a partially correlated opening of the LID and AMPbd, defining the second phase. A highly stable salt bridge D118-K136 at the LID-CORE interface, contributing substantially to the total nonbonded LID-CORE interactions, was identified as a major factor that stabilizes the open conformation. Alternative transition pathways, such as AMPbd opening following LID opening, seem unlikely, as full transition events were not observed along this pathway. The simulation data indicate a high enthalpic penalty, possibly obstructing transitions along this route.     

Fuzzy cluster analysis of molecular dynamics trajectories.

We propose fuzzy clustering as a method to analyze molecular dynamics (MD) trajectories, especially of proteins and polypeptides. A fuzzy cluster analysis locates classes of similar three-dimensional conformations explored during a molecular dynamics simulation. The method can be readily applied to results from both equilibrium and nonequilibrium simulations, with clustering on either global or local structural parameters. The potential of this technique is illustrated by results from fuzzy cluster analyses of trajectories from MD simulations of various fragments of human parathyroid hormone (PTH). For large molecules, it is more efficient to analyze the clustering of root-mean-square distances between conformations comprising the trajectory. We found that the results of the clustering analysis were unambiguous, in terms of the optimal number of clusters of conformations, for the majority of the trajectories examined. The conformation closest to the cluster center can be chosen as being representative of the class of structures making up the cluster, and can be further analyzed, for example, in terms of its secondary structure. The CPU time used by the cluster analysis was negligible compared to the MD simulation time.     

Real-time interactive frequency filtering of molecular dynamics trajectories

Molecular dynamics simulations of atomic motion in protein and nucleic acid molecules must be done on a femtosecond time-scale. Much of this rapid motion is unimportant for the slower changes that are most relevant to biological function (conformational changes, substrate binding, protein folding). The high-frequency motion makes simulations computationally expensive. More importantly, the high frequencies obscure visualization of the relevant dynamics processes. Sessions, Dauber-Osguthorpe and Osguthorpe presented a method for removing high-frequency motions from atomic co-ordinates of trajectories generated by simulation. While that study used fast Fourier methods and emphasized the use of filtering for analysis of trajectories, this communication describes a new method that makes it much easier to use frequency filtering in programs that display trajectories as a sequence of moving images. Tests of the method on systems extending from pure water to proteins and nucleic acid molecules in vacuo and in solution have demonstrated its general utility. Impressed with the power and simplicity of the new method, we wish to present it in sufficient detail to allow others to implement it themselves.     

Multiscale modeling of cellular actin filaments: from atomistic molecular to coarse-grained dynamics

In this article, we present a computational multiscale model for the characterization of subcellular proteins. The model is encoded inside a simulation tool that builds coarse-grained (CG) force fields from atomistic simulations. Equilibrium molecular dynamics simulations on an all-atom model of the actin filament are performed. Then, using the statistical distribution of the distances between pairs of selected groups of atoms at the output of the MD simulations, the force field is parameterized using the Boltzmann inversion approach. This CG force field is further used to characterize the dynamics of the protein via Brownian dynamics simulations. This combination of methods into a single computational tool flow enables the simulation of actin filaments with length up to 400 nm, extending the time and length scales compared to state-of-the-art approaches. Moreover, the proposed multiscale modeling approach allows to investigate the relationship between atomistic structure and changes on the overall dynamics and mechanics of the filament and can be easily (i) extended to the characterization of other subcellular structures and (ii) used to investigate the cellular effects of molecular alterations due to pathological conditions.     

Neon atoms oscillating inside carbon and boron nitride nanotubes: a fully atomistic molecular dynamics investigation

In the present work, based on extensive fully atomistic molecular dynamics simulations, we discuss the dynamics of neon atoms oscillating inside (5,5) single-walled carbon nanotubes (CNTs) and boron nitride nanotubes (BNNTs). Our results show that sustained high-frequency oscillatory regimes are possible for a large range of temperatures. Our results also show that the general features of the oscillations are quite similar to those observed in CNT and BNNT, in contrast with some speculations in previous works in the literature about the importance of broken symmetry and chirality exhibited by BNNTs.     

Self-assembling of peptide/membrane complexes by atomistic molecular dynamics simulations

Model biological membranes consisting of peptide/lipid-bilayer complexes can nowadays be studied by classical molecular dynamics (MD) simulations at atomic detail. In most cases, the simulation starts with an assumed state of a peptide in a preformed bilayer, from which equilibrium configurations are difficult to obtain due to a relatively slow molecular diffusion. As an alternative, we propose an extension of reported work on the self-organization of unordered lipids into bilayers, consisting of including a peptide molecule in the initial random configuration to obtain a membrane-bound peptide simultaneous to the formation of the lipid bilayer. This strategy takes advantage of the fast reorganization of lipids, among themselves and around the peptide, in an aqueous environment. Model peptides of different hydrophobicity, CH3-CO-W2L18W2-NH2 (WL22) and CH3-CO-W2A18W2-NH2 (WA22), in dipalmitoyl-phosphatidylcholine (DPPC) are used as test cases. In the equilibrium states of the peptide/membrane complexes, achieved in time ranges of 50-100 ns, the two peptides behave as expected from experimental and theoretical studies. The strongly hydrophobic WL22 is inserted in a transmembrane configuration and the marginally apolar, alanine-based WA22 is found in two alternative states: transmembrane inserted or parallel to the membrane plane, embedded close to the bilayer interface, with similar stability. This shows that the spontaneous assembly of peptides and lipids is an unbiased and reliable strategy to produce and study models of equilibrated peptide/lipid complexes of unknown membrane-binding mode and topology.     

Data mining of molecular dynamics trajectories of nucleic acids

Analysis, storage, and transfer of molecular dynamic trajectories are becoming the bottleneck of computer simulations. In this paper we discuss different approaches for data mining and data processing of huge trajectory files generated from molecular dynamic simulations of nucleic acids.     

Trajectory NG: portable, compressed, general molecular dynamics trajectories

We present general algorithms for the compression of molecular dynamics trajectories. The standard ways to store MD trajectories as text or as raw binary floating point numbers result in very large files when efficient simulation programs are used on supercomputers. Our algorithms are based on the observation that differences in atomic coordinates/velocities, in either time or space, are generally smaller than the absolute values of the coordinates/velocities. Also, it is often possible to store values at a lower precision. We apply several compression schemes to compress the resulting differences further. The most efficient algorithms developed here use a block sorting algorithm in combination with Huffman coding. Depending on the frequency of storage of frames in the trajectory, either space, time, or combinations of space and time differences are usually the most efficient. We compare the efficiency of our algorithms with each other and with other algorithms present in the literature for various systems: liquid argon, water, a virus capsid solvated in 15 mM aqueous NaCl, and solid magnesium oxide. We perform tests to determine how much precision is necessary to obtain accurate structural and dynamic properties, as well as benchmark a parallelized implementation of the algorithms. We obtain compression ratios (compared to single precision floating point) of 1:3.3–1:35 depending on the frequency of storage of frames and the system studied.     

Dynamics alignment: comparison of protein dynamics in the SCOP database

A novel methodology for comparison of protein dynamics is presented. Protein dynamics is calculated using the Gaussian network model and the modes of motion are globally aligned using the dynamic programming algorithm of Needleman and Wunsch, commonly used for sequence alignment. The alignment is fast and can be used to analyze large sets of proteins. The methodology is applied to the four major classes of the SCOP database: "all alpha proteins," "all beta proteins," "alpha and beta proteins," and "alpha/beta proteins". We show that different domains may have similar global dynamics. In addition, we report that the dynamics of "all alpha proteins" domains are less specific to structural variations within a given fold or superfamily compared with the other classes. We report that domain pairs with the most similar and the least similar global dynamics tend to be of similar length. The significance of the methodology is that it suggests a new and efficient way of mapping between the global structural features of protein families/subfamilies and their encoded dynamics.     

Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations

Bcl-X(L), an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-X(L): BH3 peptide and Bcl-X(L): SN15 peptide (a peptide derived from residues S15-N29 of p53) complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-X(L) and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4), which are occupied by four systematically spaced hydrophobic residues (h1-h4) of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2-p4) of Bcl-X(L) in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.     

Towards an understanding of complex biological membranes from atomistic molecular dynamics simulations

Computer simulation has emerged as a powerful tool for studying the structural and functional properties of complex biological membranes. In the last few years, the use of recently developed simulation methodologies and current generation force fields has permitted novel applications of molecular dynamics simulations, which have enhanced our understanding of the different physical processes governing biomembrane structure and dynamics. This review focuses on frontier areas of research with important biomedical applications. We have paid special attention to polyunsaturated lipids, membrane proteins and ion channels, surfactant additives in membranes, and lipid–DNA gene transfer complexes.     

The reaction mechanisms of heme catalases: an atomistic view by ab initio molecular dynamics

Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H(2)O(2) → 2H(2)O+O(2)) with high efficiency. The enzyme is first oxidized to a high-valent iron intermediate, known as Compound I (Cpd I, Por(·+)-Fe(IV)=O) which, at difference from other hydroperoxidases, is reduced back to the resting state by further reacting with H(2)O(2). The normal catalase activity is reduced if Cpd I is consumed in a competing side reaction, forming a species named Cpd I*. In recent years, Density Functional Theory (DFT) methods have unraveled the electronic configuration of these high-valent iron species, helping to assign the intermediates trapped in the crystal structures of oxidized catalases. It has been demonstrated that the a priori assumption that the H(+)/H(-) type of mechanism for Cpd I reduction leads to the generation of singlet oxygen is not justified. Moreover, it has been shown by ab initio metadynamics simulations that two pathways are operative for Cpd I reduction: a His-mediated mechanism (described as H·/H(+) + e(-)) in which the distal His acts as an acid-base catalyst and a direct mechanism (described as H·/H·) in which the distal His does not play a direct role. Independently of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron transfer, as previously assumed. Electron transfer to Cpd I, regardless of whether the electron is exogenous or endogenous, facilitates protonation of the oxoferryl group, to the point that formation of Cpd I* may be controlled by the easiness of protonation of reduced Cpd I.     

Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail

Presently, most simulations of ion channel function rely upon nonatomistic Brownian dynamics calculations, indirect interpretation of energy maps, or application of external electric fields. We present a computational method to directly simulate ion flux through membrane channels based on biologically realistic electrochemical gradients. In close analogy to single-channel electrophysiology, physiologically and experimentally relevant timescales are achieved. We apply our method to the bacterial channel PorB from pathogenic Neisseria meningitidis, which, during Neisserial infection, inserts into the mitochondrial membrane of target cells and elicits apoptosis by dissipating the membrane potential. We show that our method accurately predicts ion conductance and selectivity and elucidates ion conduction mechanisms in great detail. Handles for overcoming channel-related antibiotic resistance are identified.     

MD display: An interactive graphics program for visualization of molecular dynamics trajectories

MD Display was developed as a means of visualizing molecular dynamic trajectories generated by Amber.¹ The program runs on Silicon Graphics workstations, and features a simple user interface, and convenient display and analysis options. The program has now been extended to accept input from several other molecular dynamics programs.     

Molecular dynamics simulation of the atomistic monolayer structures of N-acyl amino acid-based surfactants

Abstract

Atomic molecular dynamics simulations have been performed on the monolayer systems of N-acyl amino acid-based surfactants. The role of intermolecular hydrogen bonds and ionic side chain length of dicarboxylate surfactants were investigated through radial and spatial distribution functions. It was found that the hydrogen bonding capability between surfactants was the major factor determining the surface area each surfactant could occupy. Tighter packing of surfactants would lead to a weaker interaction with water molecule, and the protonation of carboxylate groups resulted in stronger inter-surfactant interactions. The hydrogen bonds with water molecules were found to prevail between the carboxylate groups, and regular cage-like water distributions surrounding the surfactant headgroups were seen. The introduction of divalent ions leads to a significant increase of counterion binding, and their intramolecular and intermolecular bindings of calcium ions were also well characterised. The intramolecular chelation of calcium ions was found impossible between the carboxylate groups for N-acyl glutamate due to its flexible side chain.