Solute molecular dynamics in a mesoscale solvent

Photoexcitation of a solute alters the solute-solvent interaction, resulting in the nonequilibrium relaxation of the solvation structure, often called a dynamic Stokes shift or solvation dynamics. Thanks to the local nature of the solute-solvent interaction, the characteristics of the local solvent environment dissolving the solute can be captured by the observation of this process. Recently, we derived the energy-represented Smoluchowski-Vlasov (ERSV) equation, a diffusion equation for molecular liquids, which can be used to analyze the solvation dynamics on the diffusion timescale. This equation expresses the time development for the solvent distribution on the solute-solvent pair interaction energy (energy coordinate). Since the energy coordinate can effectively treat the solvent flexibility in addition to the position and orientation, the ERSV equation can be utilized in various solvent systems. Here, we apply the ERSV equation to the solvation dynamics of 6-propionyl-2-dimethylamino naphthalene (Prodan) in water and different alcohol solvents (methanol, ethanol, and 1-propanol) for clarifying the differences of the relaxation processes among these solvents. Prodan is a solvent-sensitive fluorescent probe and is thus widely utilized for investigating heterogeneous environments. On the long timescale, the ERSV equation satisfactorily reproduces the relaxation time correlation functions obtained from the molecular dynamics (MD) simulations for these solvents. We reveal that the relaxation time coefficient on the diffusion timescale linearly correlates with the inverse of the translational diffusion coefficients for the alcohol solvents because of the Prodan-solvent energy distributions among the alcohols. In the case of water, the time coefficient deviates from the linear relationship for the alcohols due to the difference in the extent of importance of the collective motion between the water and alcohol solvents.

Discrete approaches for the nonlinear analysis of in plane loaded masonry walls: Molecular dynamic and static algorithm solutions

Calculating the free energy of nearly jammed hard-particle packings using molecular dynamics

The solvent reorganization process after electronic excitation of a polar solute in a polar solvent such as acetonitrile is related mainly to the time evolution of the solute-solvent electrostatic interaction. Modern laser-based techniques have sufficient time resolution to follow this decay in real time, providing information to be confirmed and interpreted by theories and models. We present here a study aimed at the investigation of the different steps involved in the process taking place after a vertical S(0) --> S(1) excitation of a large size chromophore, coumarin 153 (C153), in acetonitrile, from both the solute and the solvent points of view. To do this, we use accurate quantum mechanical calculations for the solute properties within the polarizable continuum model (PCM) and classical molecular dynamics (MD) simulations, both equilibrium and nonequilibrium, for C153 in the presence of the solvent. The geometry of the solute is allowed to change in order to study the role of internal motions in the time-dependent solvation process. The solvent response function has been obtained from the simulation data and compared to experiment, while the comparison between equilibrium and nonequilibrium MD results for the solvation response confirms the validity of the linear response approximation in the C153-acetonitrile system. The MD trajectories have also been used to monitor the structure of the solvation shell and to determine its change in response to the change in the solute partial charges.

ProtoMol is a high-performance framework in C++ for rapid prototyping of novel algorithms for molecular dynamics and related applications. Its flexibility is achieved primarily through the use of inheritance and design patterns (object-oriented programming). Performance is obtained by using templates that enable generation of efficient code for sections critical to performance (generic programming). The framework encapsulates important optimizations that can be used by developers, such as parallelism in the force computation. Its design is based on domain analysis of numerical integrators for molecular dynamics (MD) and of fast solvers for the force computation, particularly due to electrostatic interactions. Several new and efficient algorithms are implemented in ProtoMol. Finally, it is shown that ProtoMol's sequential performance is excellent when compared to a leading MD program, and that it scales well for moderate number of processors. Binaries and source codes for Windows, Linux, Solaris, IRIX, HP-UX, and AIX platforms are available under open source license at http://protomol.sourceforge.net.

Highly concentrated electrolytes (HCEs) are attracting interest as safer and more stable alternatives to current lithium-ion battery electrolytes, but their structure, solvation dynamics and ion transport mechanisms are arguably more complex. We here present a novel general method for analyzing both the structure and the dynamics, and ultimately the ion transport mechanism(s), of electrolytes including HCEs. This is based on automated detection of bonds, both covalent and coordination bonds, including how they dynamically change, in molecular dynamics (MD) simulation trajectories. We thereafter classify distinct local structures by their bond topology and characterize their physicochemical properties by statistical mechanics, giving both a qualitative and quantitative description of the structure, solvation and coordination dynamics, and ion transport mechanism(s). We demonstrate the method by in detail analyzing an ab initio MD simulation trajectory of an HCE consisting of the LiTFSI salt dissolved in acetonitrile at a 1:2 molar ratio. We find this electrolyte to form a flexible percolating network which limits vehicular ion transport but enables the Li+ ions to move between different TFSI coordination sites along with their first solvation shells. In contrast, the TFSI anions are immobilized in the network, but often free to rotate which further facilitates the Li+ hopping mechanism.

Using the molecular dynamics method, we examine a discrete deterministic model for the motion of spherical particles in three-dimensional space. The model takes into account multiparticle collisions in arbitrary forms. Using fractional calculus we proposed an expression for the repulsive force, which is the so-called fractional interaction law. We then illustrate and discuss how to control (correlate) the energy dissipation and the collisional time for an individual particle within multiparticle collisions. We included in the multiparticle collisions the friction mechanism needed for the transition from coupled torsion-sliding friction through rolling friction to static friction. Analyzing simple simulations we found that binary collisions dominate in the strong repulsive state. However, weak repulsion is observed to be much stronger within multiparticle collisions. The presented numerical results can be used to realistically model the impact dynamics of an individual particle in a group of colliding particles.

In this chapter, we present current studies on molecular dynamics (MD) simulations of hydrogen-bonded systems with emphasis on vibrational spectra analysis. One of the most informative experimental data are spectroscopic data (infrared and Raman spectroscopy), which give information important in diverse fields, e.g. protein folding, drug design, sensors, nanotechnology, separations, etc. Spectroscopic data are very sensitive on inter- and intramolecular interactions. The processes of melting, boiling, unfolding and strand separation involve disruption of molecular interactions, that engage attractive or repulsive forces between molecules. In this chapter, we focus on calculations of IR spectra of hydrogen-bonded complexes based on linear response theory, in which the spectral density is the Fourier transform of the autocorrelation function of the dipole moment operator involved in the IR transitions. Recently, Born–Oppenheimer molecular dynamics (BOMD), Car–Parrinello molecular dynamics (CPMD), path integral molecular dynamics (PIMD), hybrid molecular dynamics (QM/MM) and other methods which use trajectories from molecular dynamics have been employed to simulate IR spectra of hydrogen-bonded systems. Each of these methods has some advantages and disadvantages which will be discussed in this chapter presenting also recent applications of these methods.

p21ras protein activity, regulated by GTP hydrolysis, constitutes an active field of research for the development of cancer targeted therapies that would concern ∼30% of human tumors to which specific mutations have been associated. Indeed, the catalyzing mechanisms provided by the protein environment during GTP hydrolysis and how they are impaired by specific mutations remain to be fully elucidated. In this article, we present results from molecular mechanics (MM) molecular dynamics (MD) simulations and density functional theory (DFT) calculations carried out for wild-type p21 N-ras and six Gln 61 mutants. In the first part, we present the water distribution within the active site of the wild-type protein according to MM MD. Significant differences are observed when comparing the results to the previous distribution assessed through quantum mechanics/molecular mechanics (QM/MM) MD. Such method-dependent results highlight the importance of accounting for the electrostatic coupling between the protein complex and the solvent molecules in identifying hydration sites. In the second part, we present the results from DFT calculations performed to determine the electronic distribution of the GTP ligand, considering the wild-type active site arrangement according to both classical and hybrid approaches. Only in the QM/MM-based configuration is the ligand electronic density similar to that of a GDP-like state observed experimentally. For this reason, in the last set of calculations carried out for p21 N-ras Gln 61 mutants, only the active site structural conformations obtained through hybrid MD are considered. Through the analysis of the GTP electronic density, we conclude that the wild-type active site arrangement according to QM/MM MD is closer to a catalytically efficient conformation of the protein than the arrangement according to MM MD. Hence, water distribution according to the hybrid approach must correspond to the optimal placement of solvent in the active site. Within all of the studied Gln 61 substituted proteins, p21ras major catalyzing effect, which consists of stabilizing a more GDP-like state, is lost.

The effects of hydrodynamic interactions on the friction tensors for two particles in solution are studied. The particles have linear dimensions on nanometer scales and are either simple spherical particles interacting with the solvent through repulsive Lennard-Jones forces or are composite cluster particles whose atomic components interact with the solvent through repulsive Lennard-Jones forces. The solvent dynamics is modeled at a mesoscopic level through multiparticle collisions that conserve mass, momentum, and energy. The dependence of the two-particle relative friction tensors on the interparticle separation indicates the importance of hydrodynamic interactions for these nanoparticles.

We propose a novel molecular dynamics (MD) algorithm for approximately dealing with a nuclear quantum dynamics in a real-time MD simulation. We have found that real-time dynamics of the ensemble of classical particles acquires quantum nature by introducing a constant quantum mechanical uncertainty constraint on its classical dynamics. The constant uncertainty constraint is handled by the Lagrange multiplier method and implemented into a conventional MD algorithm. The resulting constant uncertainty molecular dynamics (CUMD) is applied to the calculation of quantum position autocorrelation functions on quartic and Morse potentials. The test calculations show that CUMD gives better performance than ring-polymer MD because of the inclusion of the quantum zero-point energy during real-time evolution as well as the quantum imaginary-time statistical effect stored in an initial condition. The CUMD approach will be a possible starting point for new real-time quantum dynamics simulation in condensed phase.

ABSTRACTWe introduce a Discard-and-Restart molecular dynamics (MD) algorithm tailored for the sampling of realistic protein transition states. It aids computational structure-based drug discovery by reducing the simulation times to compute transition pathways by up to 2000x. The algorithm iteratively performs short MD simulations and measures their proximity to a target state via a collective variable (CV) loss, which can be defined in a flexible fashion, locally or globally. Using the loss, if the trajectory proceeds toward the target, the MD simulation continues. Otherwise, it is discarded and a new MD simulation is restarted, with new initial velocities randomly drawn from a Boltzmann distribution. The discard-and-restart algorithm demonstrates efficacy and atomistic accuracy in capturing the folding pathways in several contexts: (1) fast-folding small protein domains; (2) the folding intermediate of the prion protein PrP; and (3) the spontaneous partial unfolding of α-Tubulin, a crucial event for microtubule severing. During each iteration of the algorithm, we are able to perform AI-based analysis of the transitory conformations to find binding pockets, which could potentially represent druggable sites. Overall, our algorithm enables systematic and computationally efficient exploration of conformational landscapes, enhancing the design of ligands targeting dynamic protein states.

A discard-and-restart MD algorithm for the sampling of protein intermediate states.

The impact of temperature-induced changes in solvent dynamics on the diffusion coefficient and standard rate constant k0 for heterogeneous electron transfer (ET) of ethylferrocene (EFc) in 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6 ]) is investigated. The results are analysed to understand the impact of solvent-dynamic control, solute-solvent interactions and solvent friction on the transport of redox probes and k0 . Concentration dependence of the diffusion coefficient of EFc in [BMIM][PF6 ] is observed. This is attributed to the solute-induced enhancement of the structural organisation of the ionic liquid (IL), which is supported by the concentration-dependent UV/Vis absorption and photoluminescence responses of EFc/[BMIM][PF6 ] solutions. Similar values of the activation energies for mass transport and ET and a linear relationship between the diffusion coefficient and the heterogeneous ET rate is observed. The ratio between the diffusion coefficient and the heterogeneous rate constant allows a characteristic length Ld , which is temperature-independent, to be introduced. The presented results clearly establish that mass transport and heterogeneous ET of redox probes are strongly correlated in ILs. It is proposed that the apparent kinetics of heterogeneous ET reactions in ILs can be explained in terms of their impact on thermal equilibration, energy dissipation and thermal excitation of redox-active probes.

PEGylation is essential for the effective function of biologics, shielding them from rapid degradation and clearance in the complex environment of the human body. Despite its significance, a mechanistic understanding of PEGylation's role in enhancing protein stability is incomplete, limiting the ability to design PEGylated proteins with predictable properties. Solvation, a well-known driving force in protein folding and stability, is hypothesized to play a central role in protein stabilization via PEGylation, but molecular mechanisms underlying solvent-driven stabilization are not well understood. Here, we investigated solvent dynamics and the interactions of the solvent with the PEGylated carbohydrate recognition domain of human Galectin-3 (Gal3C) in aqueous solutions. Two-dimensional infrared (2D IR) spectroscopy, which captures subpicosecond molecular ensembles, revealed polymer length-dependent differences in protein dynamics and solvent dynamics for PEGylated Gal3C. Slower solvent dynamics correlated with increased conjugate thermal stability. Complementing these data, multidimensional nuclear magnetic resonance (NMR) spectroscopy provided evidence that Gal3C conjugated to longer PEG forms a noncovalent interaction "shroud", which correlated with changes in dynamics of the solvent and protein backbone. Molecular dynamics (MD) simulations supported an interpretation of the experimental results that PEGylation did not reduce the protein's solvent-accessible surface area. The integration of these data challenges the idea that PEGylation stabilizes conjugated proteins by dehydrating a protein's surface. Instead, these data support a mechanism where PEGylation improves protein stability by stabilizing the protein's solvation shell. These insights offer guidance for optimizing polymer length to achieve the desired thermal stability in biologics.