Histidine hydrogen bonding in MHC at pH 5 and pH 7 modeled by molecular docking and molecular dynamics simulations

Hydrogen bonds play important roles in maintaining the structure of proteins and in the formation of most biomolecular protein-ligand complexes. All amino acids can act as hydrogen bond donors and acceptors. Among amino acids, Histidine is unique, as it can exist in neutral or positively charged forms within the physiological pH range of 5.0 to 7.0. Histidine can thus interact with other aromatic residues as well as forming hydrogen bonds with polar and charged residues. The ability of His to exchange a proton lies at the heart of many important functional biomolecular interactions, including immunological ones. By using molecular docking and molecular dynamics simulation, we examine the influence of His protonation/deprotonation on peptide binding affinity to MHC class II proteins from locus HLA-DP. Peptide-MHC interaction underlies the adaptive cellular immune response, upon which the next generation of commercially-important vaccines will depend. Consistent with experiment, we find that peptides containing protonated His residues bind better to HLA-DP proteins than those with unprotonated His. Enhanced binding at pH 5.0 is due, in part, to additional hydrogen bonds formed between peptide His+ and DP proteins. In acidic endosomes, protein His79�� is predominantly protonated. As a result, the peptide binding cleft narrows in the vicinity of His79��, which stabilizes the peptide - HLA-DP protein complex. �� 2014 Bentham Science Publishers.

Multiscale molecular dynamics/hydrodynamics implementation of two dimensional ���Mercedes Benz��� water model

A multiscale Molecular Dynamics/Hydrodynamics implementation of the 2D Mercedes Benz (MB or BN2D) [1] water model is developed and investigated. The concept and the governing equations of multiscale coupling together with the results of the two-way coupling implementation are reported. The sensitivity of the multiscale model for obtaining macroscopic and microscopic parameters of the system, such as macroscopic density and velocity fluctuations, radial distribution and velocity autocorrelation functions of MB particles, is evaluated. Critical issues for extending the current model to large systems are discussed.

A hybrid molecular dynamics/fluctuating hydrodynamics method for modelling liquids at multiple scales in space and time

A new 3D implementation of a hybrid model based on the analogy with two-phase hydrodynamics has been developed for the simulation of liquids at microscale. The idea of the method is to smoothly combine the atomistic description in the molecular dynamics zone with the Landau-Lifshitz fluctuating hydrodynamics representation in the rest of the system in the framework of macroscopic conservation laws through the use of a single "zoom-in" user-defined function s that has the meaning of a partial concentration in the two-phase analogy model. In comparison with our previous works, the implementation has been extended to full 3D simulations for a range of atomistic models in GROMACS from argon to water in equilibrium conditions with a constant or a spatially variable function s. Preliminary results of simulating the diffusion of a small peptide in water are also reported.

Self-healing of cracks during ductile regime machining of silicon: Insights from molecular dynamics simulation

During nanoindentation and ductile-regime machining of silicon, a phenomenon known as ���self-healing��� takes place in that the microcracks, microfractures, and small spallings generated during the machining are filled by the plastically flowing ductile phase of silicon. However, this phenomenon has not been observed in simulation studies. In this work, using a long-range potential function, molecular dynamics simulation was used to provide an improved explanation of this mechanism. A unique phenomenon of brittle cracking was discovered, typically inclined at an angle of 45�� to 55�� to the cut surface, leading to the formation of periodic arrays of nanogrooves being filled by plastically flowing silicon during cutting. This observation is supported by the direct imaging. The simulated X-ray diffraction analysis proves that in contrast to experiments, Si-I to Si-II (beta tin) transformation during ductile-regime cutting is highly unlikely and solid-state amorphisation of silicon caused solely by the machining stress rather than the cutting temperature is the key to its brittle-ductile transition observed during the MD simulations

Analysis of Molecular Dynamics Simulations of Protein Folding

Microsecond long Molecular Dynamics (MD) trajectories of biomolecular processes are now possible due to advances in computer technology. Soon, trajectories long enough to probe dynamics over many milliseconds will become available. Since these timescales match the physiological timescales over which many small proteins fold, all atom MD simulations of protein folding are now becoming popular. To distill features of such large folding trajectories, we must develop methods that can both compress trajectory data to enable visualization, and that can yield themselves to further analysis, such as the finding of collective coordinates and reduction of the dynamics. Conventionally, clustering has been the most popular MD trajectory analysis technique, followed by principal component analysis (PCA). Simple clustering used in MD trajectory analysis suffers from various serious drawbacks, namely, (i) it is not data driven, (ii) it is unstable to noise and change in cutoff parameters, and (iii) since it does not take into account interrelationships amongst data points, the separation of data into clusters can often be artificial. Usually, partitions generated by clustering techniques are validated visually, but such validation is not possible for MD trajectories of protein folding, as the underlying structural transitions are not well understood. Rigorous cluster validation techniques may be adapted, but it is more crucial to reduce the dimensions in which MD trajectories reside, while still preserving their salient features. PCA has often been used for dimension reduction and while it is computationally inexpensive, being a linear method, it does not achieve good data compression. In this thesis, I propose a different method, a nonmetric multidimensional scaling (nMDS) technique, which achieves superior data compression by virtue of being nonlinear, and also provides a clear insight into the structural processes underlying MD trajectories. I illustrate the capabilities of nMDS by analyzing three complete villin headpiece folding and six norleucine mutant (NLE) folding trajectories simulated by Freddolino and Schulten [1]. Using these trajectories, I make comparisons between nMDS, PCA and clustering to demonstrate the superiority of nMDS. The three villin headpiece trajectories showed great structural heterogeneity. Apart from a few trivial features like early formation of secondary structure, no commonalities between trajectories were found. There were no units of residues or atoms found moving in concert across the trajectories. A flipping transition, corresponding to the flipping of helix 1 relative to the plane formed by helices 2 and 3 was observed towards the end of the folding process in all trajectories, when nearly all native contacts had been formed. However, the transition occurred through a different series of steps in all trajectories, indicating that it may not be a common transition in villin folding. The trajectories showed competition between local structure formation/hydrophobic collapse and global structure formation in all trajectories. Our analysis on the NLE trajectories confirms the notion that a tight hydrophobic core inhibits correct 3-D rearrangement. Only one of the six NLE trajectories folded, and it showed no flipping transition. All the other trajectories get trapped in hydrophobically collapsed states. The NLE residues were found to be buried deeply into the core, compared to the corresponding lysines in the villin headpiece, thereby making the core tighter and harder to undo for 3-D rearrangement. Our results suggest that the NLE may not be a fast folder as experiments suggest. The tightness of the hydrophobic core may be a very important factor in the folding of larger proteins. It is likely that chaperones like GroEL act to undo the tight hydrophobic core of proteins, after most secondary structure elements have been formed, so that global rearrangement is easier. I conclude by presenting facts about chaperone-protein complexes and propose further directions for the study of protein folding.

Data of the molecular dynamics simulations of mutations in the human connexin46 docking interface

The structure of hCx26 derived from the X-ray analysis was used to generate a homology model for hCx46. Interacting connexin molecules were used as starting model for the molecular dynamics (MD) simulation using NAMD and allowed us to predict the dynamic behavior of hCx46wt and the cataract related mutant hCx46N188T as well as two artificial mutants hCx46N188Q and hCx46N188D. Within the 50 ns simulation time the docked complex composed of the mutants dissociate while hCx46wt remains stable. The data indicates that one hCx46 molecule forms 5-7 hydrogen bonds (HBs) with the counterpart connexin of the opposing connexon. These HBs appear essential for a stable docking of the connexons as shown by the simulation of an entire gap junction channel and were lost for all the tested mutants. The data described here are related to the research article entitled "The cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels" (Schadzek et al., 2015) [1].

PARAMETRIC STUDY OF REAXFF SIMULATION PARAMETERS FOR MOLECULAR DYNAMICS MODELING OF REACTIVE CARBON GASES

Abstract The development of innovative carbon-based materials can be greatly facilitated by molecular modeling techniques. Although the Reax Force Field (ReaxFF) can be used to simulate the chemical behavior of carbon-based systems, the simulation settings required for accurate predictions have not been fully explored. Using the ReaxFF, molecular dynamics (MD) simulations are used to simulate the chemical behavior of pure carbon and hydrocarbon reactive gases that are involved in the formation of carbon structures such as graphite, buckyballs, amorphous carbon, and carbon nanotubes. It is determined that the maximum simulation time step that can be used in MD simulations with the ReaxFF is dependent on the simulated temperature and selected parameter set, as are the predicted reaction rates. It is also determined that different carbon-based reactive gases react at different rates, and that the predicted equilibrium structures are generally the same for the different ReaxFF parameter sets, except in the case of the predicted formation of large graphitic structures with the Chenoweth parameter set under specific conditions.

Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study

Fluorescence spectroscopy andmicroscopy have been utilized as tools in membrane biophysics for decades now. Because phospholipids are non-fluorescent, the use of extrinsic membrane probes in this context is commonplace. Among the latter, 1,6-diphenylhexatriene (DPH) and its trimethylammonium derivative (TMA-DPH) have been extensively used. It is widely believed that, owing to its additional charged group, TMA-DPH is anchored at the lipid/water interface and reports on a bilayer region that is distinct from that of the hydrophobic DPH. In this study, we employ atomistic MD simulations to characterize the behavior of DPH and TMA-DPH in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and POPC/cholesterol (4:1) bilayers. We show that although the dynamics of TMA-DPH in thesemembranes is noticeably more hindered than that of DPH, the location of the average fluorophore of TMA-DPH is only ~3���4 �� more shallow than that of DPH. The hindrance observed in the translational and rotational motions of TMA-DPH compared to DPH is mainly not due to significant differences in depth, but to the favorable electrostatic interactions of the former with electronegative lipid atoms instead. By revealing detailed insights on the behavior of these two probes, our results are useful both in the interpretation of past work and in the planning of future experiments using themasmembrane reporters.

Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study

Fluorescence spectroscopy andmicroscopy have been utilized as tools in membrane biophysics for decades now. Because phospholipids are non-fluorescent, the use of extrinsic membrane probes in this context is commonplace. Among the latter, 1,6-diphenylhexatriene (DPH) and its trimethylammonium derivative (TMA-DPH) have been extensively used. It is widely believed that, owing to its additional charged group, TMA-DPH is anchored at the lipid/water interface and reports on a bilayer region that is distinct from that of the hydrophobic DPH. In this study, we employ atomistic MD simulations to characterize the behavior of DPH and TMA-DPH in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and POPC/cholesterol (4:1) bilayers. We show that although the dynamics of TMA-DPH in thesemembranes is noticeably more hindered than that of DPH, the location of the average fluorophore of TMA-DPH is only ~3���4 �� more shallow than that of DPH. The hindrance observed in the translational and rotational motions of TMA-DPH compared to DPH is mainly not due to significant differences in depth, but to the favorable electrostatic interactions of the former with electronegative lipid atoms instead. By revealing detailed insights on the behavior of these two probes, our results are useful both in the interpretation of past work and in the planning of future experiments using themasmembrane reporters.

Studying the alignment of 5-cyanobiphenyl on a polydimethylsiloxane surface through Molecular Dynamics simulations

For 40 years, at the University of Bologna, a group of researchers coordinated by professor Claudio Zannoni has been studying liquid crystals by employing computational techniques. They have developed effective models of these interesting, and still far from being completely understood, systems. They were able to reproduce with simulations important features of some liquid crystal molecules, such as transition temperature. Then they focused their attention on the interactions that these molecules have with different kinds of surface, and how these interactions affect the alignment of liquid crystals. The group studied the behaviour of liquid crystals in contact with different kinds of surfaces, from silica, either amorphous and crystalline, to organic self assembled monolayers (SAMs) and even some common polymers, such as polymethylmethacrylate (PMMA) and polystyrene (PS). Anyway, a library of typical surfaces is still far from being complete, and a lot of work must be done to investigate the cases which have not been analyzed yet. A hole that must be filled is represented by polydimethylsiloxane (PDMS), a polymer on which the interest of industry has enormously grown up in the last years, thanks to its peculiar features, allowing it to be employed in many fields of applications. It has been observed experimentally that PDMS causes 4-cyano-4���-pentylbiphenyl (well known as 5CB), one of the most common liquid crystal molecules, to align homeotropically (i.e. perpendicular) with respect to a surface made of this polymer. Even though some hypothesis have been presented to rationalize the effect, a clear explanation of this phenomenon has not been given yet. This dissertation shows the work I did during my internship in the group of professor Zannoni. The challenge that I had to tackle was to investigate, via Molecular Dynamics (MD) simulations, the reasons of 5CB homeotropic alignment on a PDMS surface, as the group had previously done for other surfaces.

Ring flexibility within tricyclic antidepressant drugs

The internal flexibility of the central seven-membered ring of a series of tricyclic antidepressant drugs (TCAs), imipramine {l}, amitriptyline {2}, doxepin {3}, and dothiepin {4}, has been investigated by H-1 and C-13 nuclear magnetic (NMR) techniques. Two dynamic processes were examined: ring inversion and bridge flexing. H-1 NMR lineshape analysis was used to obtain ring inversion barriers for 2-4. These studies yielded energy barriers of 14.3, 16.7, and 15.7 +/- 0.6 kcal/mol for the hydrochloride salts of doxepin, dothiepin, and amitriptyline, respectively. The barriers for the corresponding free bases were lower by 0.6 kcal/mol on average. (CT1)-C-13 relaxation measurements were used to determine the degree of bridge flexing associated with the central seven-membered ring for all four compounds. By fitting the T-1 data to a two-state jump model, lifetimes and amplitudes of rapid bridge flexing motions were determined. The results show that imipramine has the fastest rate of bridge flexing, followed by amitriptyline, doxepin, and dothiepin. The pharmacological profiles of the TCAs are complex and they interact with many receptor sites, resulting in numerous side effects and a general lack of understanding of their precise mode of action in different anxiety-related disorders. They all have similar three-dimensional structures, which makes it difficult to rationalize their differing relative potency in different assays/clinical settings. However, the clear finding here that there are significantly different degrees of internal mobility suggests that molecular dynamics should be an additional factor considered when trying to understand the mode of action of this clinically important family of molecules. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:713-721, 2001.

Development of novel brush-type chiral stationary phases based on terpenoid selectors: HPLC evaluation and theoretical investigation of enantioselective binding interactions

The terpenoid chiral selectors dehydroabietic acid, 12,14-dinitrodehydroabietic acid and friedelin have been covalently linked to silica gel yielding three chiral stationary phases CSP 1, CSP 2 and CSP 3, respectively. The enantiodiscriminating capability of each one of these phases was evaluated by HPLC with four families of chiral aromatic compounds composed of alcohols, amines, phenylalanine and tryptophan amino acid derivatives and beta-lactams. The CSP 3 phase, containing a selector with a large friedelane backbone is particularly suitable for resolving free alcohols and their derivatives bearing fluorine substituents, while CSP 2 with a dehydroabietic architecture is the only phase that efficiently discriminates 1, 1'-binaphthol atropisomers. CSP 3 also gives efficient resolution of the free amines. All three phases resolve well the racemates of N-trifluoracetyl and N-3,5-dinitrobenzoyl phenylalanine amino acid ester derivatives. Good enantioseparation of beta-lactams and N-benzoyl tryptophan amino acid derivatives was achieved on CSP 1. In order to understand the structural factors that govern the chiral molecular recognition ability of these phases, molecular dynamics simulations were carried out in the gas phase with binary diastereomeric complexes formed by the selectors of CSP 1 and CSP 2 and several amino acid derivatives. Decomposition of molecular mechanics energies shows that van der Waals interactions dominate the formation of the diastereomeric transient complexes while the electrostatic binding interactions are primarily responsible for the enantioselective binding of the (R)- and (S)-analytes. Analysis of the hydrogen bonds shows that electrostatic interactions are mainly associated with the formation of N-(HO)-O-...=C enantio selective hydrogen bonds between the amide binding sites from the selectors and the carbonyl groups of the analytes. The role of mobile phase polarity, a mixture of n-hexane and propan-2-ol in different ratios, was also evaluated through molecular dynamics simulations in explicit solvent. (c) 2006 Elsevier Ltd. All rights reserved.

Molecular details of INH-C-10 binding to wt KatG and Its S315T mutant

Isoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C10, a new acylated INH derivative. MD simulations were used to explore the conformational space of both proteins, and results indicate that the S315T mutation did not have a significant impact on the average size of the access tunnel in the vicinity of these residues. Our simulations also indicate that the steric hindrance role assigned to Asp137 is transient and that electrostatic changes can be important in understanding the enzyme activity data of mutations in KatG. Additionally, molecular docking studies were used to determine the preferred modes of binding of the two substrates. Upon mutation, the apparently less favored docking solution for reaction became the most abundant, suggesting that S315T mutation favors less optimal binding modes. Moreover, the aliphatic tail in INH-C10 seems to bring the hydrazine group closer to the heme, thus favoring the apparent most reactive binding mode, regardless of the enzyme form. The ITC data is in agreement with our interpretation of the C10 alkyl chain role and helped to rationalize the significantly lower experimental MIC value observed for INH-C10. This compound seems to be able to counterbalance most of the conformational restrictions introduced by the mutation, which are thought to be responsible for the decrease in INH activity in the mutated strain. Therefore, INH-C10 appears to be a very promising lead compound for drug development.

Treatment of nonlinear optical properties due to large amplitude anharmonic vibrational motions: umbrella motion in NH3

A general reduced dimensionality finite field nuclear relaxation method for calculating vibrational nonlinear optical properties of molecules with large contributions due to anharmonic motions is introduced. In an initial application to the umbrella (inversion) motion of NH3 it is found that difficulties associated with a conventional single well treatment are overcome and that the particular definition of the inversion coordinate is not important. Future applications are described