Exploring the Effects of Methylation on the CID of Protonated Lysine: A Combined Experimental and Computational Approach.

We report the results of experiments, simulations, and DFT calculations that focus on describing the reaction dynamics observed within the collision-induced dissociation of l-lysine-H+ and its side-chain methylated analogues, Nε-methyl-l-lysine-H+ (Me1-lysine-H+), Nε,Nε-dimethyl-l-lysine-H+ (Me2-lysine-H+), and Nε,Nε,Nε-trimethyl-l-lysine-H+ (Me3-lysine-H+). The major pathways observed in the experimental measurements were m/z 130 and 84, with the former dominant at low collision energies and the latter at intermediate to high collision energies. The m/z 130 peak corresponds to loss of N(CH3)nH3-n, while m/z 84 has the additional loss of H2CO2 likely in the form of H2O + CO. Within the time frame of the direct dynamics simulations, m/z 130 and 101 were the most populous peaks, with the latter identified as an intermediate to m/z 84. The simulations allowed for the determination of several reaction pathways that result in these products. A graph theory analysis enabled the elucidation of the significant structures that compose each peak. Methylation results in the preferential loss of the side-chain amide group and a reduction of cyclic structures within the m/z 84 peak population in simulations.

AutoMeKin2021: An open-source program for automated reaction discovery.

AutoMeKin2021 is an updated version of tsscds2018, a program for the automated discovery of reaction mechanisms (J. Comput. Chem. 2018, 39, 1922). This release features a number of new capabilities: rare-event molecular dynamics simulations to enhance reaction discovery, extension of the original search algorithm to study van der Waals complexes, use of chemical knowledge, a new search algorithm based on bond-order time series analysis, statistics of the chemical reaction networks, a web application to submit jobs, and other features. The source code, manual, installation instructions and the website link are available at: https://rxnkin.usc.es/index.php/AutoMeKin.

Role of Chemical Dynamics Simulations in Mass Spectrometry Studies of Collision-Induced Dissociation and Collisions of Biological Ions with Organic Surfaces.

In this article, a perspective is given of chemical dynamics simulations of collisions of biological ions with surfaces and of collision-induced dissociation (CID) of ions. The simulations provide an atomic-level understanding of the collisions and, overall, are in quite good agreement with experiment. An integral component of ion/surface collisions is energy transfer to the internal degrees of freedom of both the ion and the surface. The simulations reveal how this energy transfer depends on the collision energy, incident angle, biological ion, and surface. With energy transfer to the ion's vibration fragmentation may occur, i.e. surface-induced dissociation (SID), and the simulations discovered a new fragmentation mechanism, called shattering, for which the ion fragments as it collides with the surface. The simulations also provide insight into the atomistic dynamics of soft-landing and reactive-landing of ions on surfaces. The CID simulations compared activation by multiple "soft" collisions, resulting in random excitation, versus high energy single collisions and nonrandom excitation. These two activation methods may result in different fragment ions. Simulations provide fragmentation products in agreement with experiments and, hence, can provide additional information regarding the reaction mechanisms taking place in experiment. Such studies paved the way on using simulations as an independent and predictive tool in increasing fundamental understanding of CID and related processes.

Modeling the Effects of O-Sulfonation on the CID of Serine.

We present the results of direct dynamics simulations and DFT calculations aimed at elucidating the effect of O-sulfonation on the collision-induced dissociation for serine. Toward this end, direct dynamics simulations of both serine and sulfoserine were performed at multiple collision energies and theoretical mass spectra obtained. Comparisons to experimental results are favorable for both systems. Peaks related to the sulfo group are identified and the reaction dynamics explored. In particular, three significant peaks (m/z 106, 88, and 81) seen in the theoretical mass spectrum directly related to the sulfo group are analyzed as well as major peaks shared by both systems. Our analysis shows that the m/z 106 peaks result from intramolecular rearrangements, intermolecular proton transfer among complexes composed of initial fragmentation products, and at high energy side-chain fragmentation. The m/z 88 peak was found to contain multiple constitutional isomers, including a previously unconsidered, low energy structure. It was also observed that the RM1 semiempirical method was not able to obtain all of the major peaks seen in experimens for sulfoserine. In contrast, PM6 did obtain all major experimental peaks.

A Computational Comparison of Soft Landing of α-Helical vs Globular Peptides.

The effect of secondary structure on the soft landing process is investigated through direct dynamics simulations of AcA7K and AcKA7 colliding with a fluorinated, organic self-assembled monolayer (FSAM) surface. The α-helical (AcA7K) and globular (AcKA7) peptides each exhibited a similar probability of soft landing with normal incidence at all collision energies considered. Rapid conformational changes were quantified through the calculation of the time dependent, conformational entropy production that took place during the collision events, which is consistent with the prior structural measurements made by Laskin and co-workers on these systems. AcA7K produces more entropy during the collisions than AcKA7.

Direct Chemical Dynamics Simulations.

In a direct dynamics simulation, the technologies of chemical dynamics and electronic structure theory are coupled so that the potential energy, gradient, and Hessian required from the simulation are obtained directly from the electronic structure theory. These simulations are extensively used to (1) interpret experimental results and understand the atomic-level dynamics of chemical reactions; (2) illustrate the ability of classical simulations to correctly interpret and predict chemical dynamics when quantum effects are expected to be unimportant; (3) obtain the correct classical dynamics predicted by an electronic structure theory; (4) determine a deeper understanding of when statistical theories are valid for predicting the mechanisms and rates of chemical reactions; and (5) discover new reaction pathways and chemical dynamics. Direct dynamics simulation studies are described for bimolecular SN2 nucleophilic substitution, unimolecular decomposition, post-transition-state dynamics, mass spectrometry experiments, and semiclassical vibrational spectra. Also included are discussions of quantum effects, the accuracy of classical chemical dynamics simulation, and the methodology of direct dynamics.

Model Simulations of the Thermal Dissociation of the TIK(H+)2 Tripeptide: Mechanisms and Kinetic Parameters.

Direct dynamics simulations, utilizing the RM1 semiempirical electronic structure theory, were performed to study the thermal dissociation of the doubly protonated tripeptide threonine-isoleucine-lysine ion, TIK(H+)2, for temperatures of 1250-2500 K, corresponding to classical energies of 1778-3556 kJ/mol. The number of different fragmentation pathways increases with increase in temperature. At 1250 K there are only three fragmentation pathways, with one contributing 85% of the fragmentation. In contrast, at 2500 K, there are 61 pathways, and not one dominates. The same ion is often formed via different pathways, and at 2500 K there are only 14 m/z values for the product ions. The backbone and side-chain fragmentations occur by concerted reactions, with simultaneous proton transfer and bond rupture, and also by homolytic bond ruptures without proton transfer. For each temperature the TIK(H+)2 fragmentation probability versus time is exponential, in accord with the Rice-Ramsperger-Kassel-Marcus and transition state theories. Rate constants versus temperature were determined for two proton transfer and two bond rupture pathways. From Arrhenius plots activation energies Ea and A-factors were determined for these pathways. They are 62-78 kJ/mol and (2-3) × 1012 s-1 for the proton transfer pathways and 153-168 kJ/mol and (2-4) × 1014 s-1 for the bond rupture pathways. For the bond rupture pathways, the product cation radicals undergo significant structural changes during the bond rupture as a result of hydrogen bonding, which lowers their entropies and also their Ea and A parameters relative to those for C-C bond rupture pathways in hydrocarbon molecules. The Ea values determined from the simulation Arrhenius plots are in very good agreement with the reaction barriers for the RM1 method used in the simulations. A preliminary simulation of TIK(H+)2 collision-induced dissociation (CID), at a collision energy of 13 eV (1255 kJ/mol), was also performed to compare with the thermal dissociation simulations. Though the energy transferred to TIK(H+)2 in the collisions is substantially less than the energy for the thermal excitations, there is substantial fragmentation as a result of the localized, nonrandom excitation by the collisions. CID results in different fragmentation pathways with a significant amount of short time nonstatistical fragmentation. Backbone fragmentation is less important, and side-chain fragmentation is more important for the CID simulations as compared to the thermal simulations. The thermal simulations provide information regarding the long-time statistical fragmentation.

Dynamics of Protonated Peptide Ion Collisions with Organic Surfaces: Consonance of Simulation and Experiment.

In this Perspective, mass spectrometry experiments and chemical dynamics simulations are described that have explored the atomistic dynamics of protonated peptide ions, peptide-H(+), colliding with organic surfaces. These studies have investigated the energy transfer and fragmentation dynamics for peptide-H(+) surface-induced dissociation (SID), peptide-H(+) physisorption on the surface, soft landing (SL), and peptide-H(+) reaction with the surface, reactive landing (RL). SID provides primary structures of biological ions and information regarding their fragmentation pathways and energetics. Two SID mechanisms are found for peptide-H(+) fragmentation. A traditional mechanism in which peptide-H(+) is vibrationally excited by its collision with the surface, rebounds off the surface and then dissociates in accord with the statistical, RRKM unimolecular rate theory. The other, shattering, is a nonstatistical mechanism in which peptide-H(+) fragments as it collides with the surface, dissociating via many pathways and forming many product ions. Shattering is important for collisions with diamond and perfluorinated self-assembled monolayer (F-SAM) surfaces, increasing in importance with the peptide-H(+) collision energy. Chemical dynamics simulations also provide important mechanistic insights on SL and RL of biological ions on surfaces. The simulations indicate that SL occurs via multiple mechanisms consisting of sequences of peptide-H(+) physisorption on and penetration in the surface. SL and RL have a broad range of important applications including preparation of protein or peptide microarrays, development of biocompatible substrates and biosensors, and preparation of novel synthetic materials, including nanomaterials. An important RL mechanism is intact deposition of peptide-H(+) on the surface.

Chemical dynamics simulations of energy transfer, surface-induced dissociation, soft-landing, and reactive-landing in collisions of protonated peptide ions with organic surfaces.

There are two components to the review presented here regarding simulations of collisions of protonated peptide ions peptide-H(+) with organic surfaces. One is a detailed description of the classical trajectory chemical dynamics simulation methodology. Different simulation approaches are used, and identified as MM, QM + MM, and QM/MM dependent on the potential energy surface used to represent the peptide-H(+) + surface collision. The second are representative examples of the information that may be obtained from the simulations regarding energy transfer and peptide-H(+) surface-induced dissociation, soft-landing, and reactive-landing for the peptide-H(+) + surface collisions. Good agreement with experiment is obtained for each of these four collision properties. The simulations provide atomistic interpretations of the peptide-H(+) + surface collision dynamics.

Energy and temperature dependent dissociation of the Na(+)(benzene)1,2 clusters: importance of anharmonicity.

Chemical dynamics simulations were performed to study the unimolecular dissociation of randomly excited Na(+)(Bz) and Na(+)(Bz)2 clusters; Bz = benzene. The simulations were performed at constant energy, and temperatures in the range of 1200-2200 K relevant to combustion, using an analytic potential energy surface (PES) derived in part from MP2/6-311+G* calculations. The clusters decompose with exponential probabilities, consistent with RRKM unimolecular rate theory. Analyses show that intramolecular vibrational energy redistribution is sufficiently rapid within the clusters that their unimolecular dynamics is intrinsically RRKM. Arrhenius parameters, determined from the simulations of the clusters, are unusual in that Ea is ∼10 kcal/mol lower the Na(+)(Bz) → Na(+) + Bz dissociation energy and the A-factor is approximately two orders-of-magnitude too small. Analyses indicate that temperature dependent anharmonicity is important for the Na(+)(Bz) cluster's unimolecular rate constants k(T). This is consistent with the temperature dependent anharmonicity found for the Na(+)(Bz) cluster from a Monte Carlo calculation based on the analytic PES used for the simulations. Apparently temperature dependent anharmonicity is quite important for unimolecular dissociation of the Na(+)(Bz)1,2 clusters.

Time dependent quantum thermodynamics of a coupled quantum oscillator system in a small thermal environment.

Simulations are performed of a small quantum system interacting with a quantum environment. The system consists of various initial states of two harmonic oscillators coupled to give normal modes. The environment is "designed" by its level pattern to have a thermodynamic temperature. A random coupling causes the system and environment to become entangled in the course of time evolution. The approach to a Boltzmann distribution is observed, and effective fitted temperatures close to the designed temperature are obtained. All initial pure states of the system are driven to equilibrium at very similar rates, with quick loss of memory of the initial state. The time evolution of the von Neumann entropy is calculated as a measure of equilibration and of quantum coherence. It is pointed out using spatial density distribution plots that quantum interference is eliminated only with maximal entropy, which corresponds thermally to infinite temperature. Implications of our results for the notion of "classicalizing" behavior in the approach to thermal equilibrium are briefly considered.

Visualizing the zero order basis of the spectroscopic Hamiltonian.

Recent works have shown that a generalization of the spectroscopic effective Hamiltonian can describe spectra in surprising regions, such as isomerization barriers. In this work, we seek to explain why the effective Hamiltonian is successful where there was reason to doubt that it would work at all. All spectroscopic Hamiltonians have an underlying abstract zero-order basis (ZOB) which is the "ideal" basis for a given form and parameterization of the Hamiltonian. Without a physical model there is no way to transform this abstract basis into a coordinate representation. To this end, we present a method of obtaining the coordinate space representation of the abstract ZOB of a spectroscopic effective Hamiltonian. This method works equally well for generalized effective Hamiltonians that encompass above-barrier multiwell behavior, and standard effective Hamiltonians for the vicinity of a single potential minimum. Our approach relies on a set of converged eigenfunctions obtained from a variational calculation on a potential surface. By making a one-to-one correspondence between the energy eigenstates of the effective Hamiltonian and those of the coordinate space Hamiltonian, a physical representation of the abstract ZOB is calculated. We find that the ZOB basis naturally adjusts its complexity depending on the underlying nature of phase space, which allows spectroscopic Hamiltonians to succeed for systems sampling multiple stationary points.

Effective Hamiltonian for femtosecond vibrational dynamics.

Time propagation of zero-order states of an effective spectroscopic Hamiltonian is tested against femtosecond time dependent dynamics of adiabatic wavepackets evolving on a model potential energy surface for two coupled modes of the radical HO(2) with multiple potential wells and above barrier motion. A generalized Hamiltonian which breaks the usual conserved polyad action by including extra resonance couplings (V(2:1) and V(3:1)) successfully describes the time evolution after the further addition of two "ultrafast" couplings. These new couplings are a nonresonant coupling a(1)a(2)+a(1)(†)a(2)(†) and a resonant coupling V(1:1) that functions as an ultrafast term because the system is far from 1:1 frequency resonance.

Fragmentation and reactivity in collisions of protonated diglycine with chemically modified perfluorinated alkylthiolate-self-assembled monolayer surfaces.

Direct dynamics simulations are reported for quantum mechanical (QM)/molecular mechanical (MM) trajectories of N-protonated diglycine (gly(2)-H(+)) colliding with chemically modified perfluorinated octanethiolate self-assembled monolayer (SAM) surfaces. The RM1 semiempirical theory is used for the QM component of the trajectories. RM1 activation and reaction energies were compared with those determined from higher-level ab initio theories. Two chemical modifications are considered in which a head group (-COCl or -CHO) is substituted on the terminal carbon of a single chain of the SAM. These surfaces are designated as the COCl-SAM and CHO-SAM, respectively. Fragmentation, peptide reaction with the SAM, and covalent linkage of the peptide or its fragments with the SAM surface are observed. Peptide fragmentation via concerted CH(2)-CO bond breakage is the dominant pathway for both surfaces. HCl formation is the dominant species produced by reaction with the COCl-SAM, while for the CHO-SAM a concerted H-atom transfer from the CHO-SAM to the peptide combined with either a H-atom or radical transfer from the peptide to the surface to form singlet reaction products is the dominant pathway. A strong collision energy dependence is found for the probability of peptide fragmentation, its reactivity, and linkage with the SAM. Surface deposition, i.e., covalent linkage between the surface and the peptide, is compared to recent experimental observations of such bonding by Laskin and co-workers [Phys. Chem. Chem. Phys. 10, 1512 (2008)]. Qualitative differences in reactivity are seen between the COCl-SAM and CHO-SAM showing that chemical identity is important for surface reactivity. The probability of reactive surface deposition, which is most closely analogous to experimental observables, peaks at a value of around 20% for a collision energy of 50 eV.

Detailed analysis of polyad-breaking spectroscopic Hamiltonians for multiple minima with above barrier motion: isomerization in HO2.

We present a two-dimensional model for isomerization in the hydroperoxyl radical (HO(2)). We then show that spectroscopic fitting Hamiltonians are capable of reproducing large scale vibrational structure above isomerization barriers. Two resonances, the 2:1 and 3:1, are necessary to describe the pertinent physical features of the system and, hence, a polyad-breaking Hamiltonian is required. We further illustrate, through the use of approximate wave functions, that inclusion of additional coupling terms yields physically unrealistic results despite an improved agreement with the exact energy levels. Instead, the use of a single diagonal term, rather than "extra" couplings, yields good fits with realistic results. Insight into the dynamical nature of isomerization is also gained through classical trajectories. Contrary to physical intuition the bend mode is not the initial "reaction mode," but rather isomerization requires excitation in both the stretch and bend modes. The dynamics reveals a Farey tree formed between the 2:1 and 3:1 resonances with the prominent 5:2 (2:1 + 3:1) feature effectively dividing the tree into portions. The 3:1 portion is associated with isomerization, while the 2:1 portion leads to "localization" and perhaps dissociation at higher energies than those considered in this work. Simple single resonance models analyzed on polyad phase spheres are able to account in a qualitative way for the spectral, periodic orbit, and wave function patterns that we observe.

Communication: Effective spectroscopic Hamiltonian for multiple minima with above barrier motion: Isomerization in HO(2).

We present a two-dimensional potential surface for the isomerization in the hydroperoxyl radical HO(2) and calculate the vibrational spectrum. We then show that a simple effective spectroscopic fitting Hamiltonian is capable of reproducing large scale vibrational spectral structure above the isomerization barrier. Polyad breaking with multiple resonances is necessary to adequately describe the spectral features of the system. Insight into the dynamical nature of isomerization related to the effective Hamiltonian is gained through classical trajectories on the model potential. Contrary to physical intuition, the bend mode is not a "reaction mode," but rather isomerization requires excitation in both stretch and bend. The dynamics reveals a Farey tree formed from the 2:1 and 3:1 resonances, corresponding to the resonance coupling terms in the effective Hamiltonian, with the prominent 5:2 (2:1+3:1) feature dividing the tree into parts that we call the 3:1 and 2:1 portions.

Model non-equilibrium molecular dynamics simulations of heat transfer from a hot gold surface to an alkylthiolate self-assembled monolayer.

Model non-equilibrium molecular dynamics (MD) simulations are presented of heat transfer from a hot Au {111} substrate to an alkylthiolate self-assembled monolayer (H-SAM) to assist in obtaining an atomic-level understanding of experiments by Wang et al. (Z. Wang, J. A. Carter, A. Lagutchev, Y. K. Koh, N.-H. Seong, D. G. Cahill, and D. D. Dlott, Science, 2007, 317, 787). Different models are considered to determine how they affect the heat transfer dynamics. They include temperature equilibrated (TE) and temperature gradient (TG) thermostat models for the Au(s) surface, and soft and stiff S/Au(s) models for bonding of the S-atoms to the Au(s) surface. A detailed analysis of the non-equilibrium heat transfer at the heterogeneous interface is presented. There is a short time temperature gradient within the top layers of the Au(s) surface. The S-atoms heat rapidly, much faster than do the C-atoms in the alkylthiolate chains. A high thermal conductivity in the H-SAM, perpendicular to the interface, results in nearly identical temperatures for the CH(2) and CH(3) groups versus time. Thermal-induced disorder is analyzed for the Au(s) substrate, the S/Au(s) interface and the H-SAM. Before heat transfer occurs from the hot Au(s) substrate to the H-SAM, there is disorder at the S/Au(s) interface and within the alkylthiolate chains arising from heat-induced disorder near the surface of hot Au(s). The short-time rapid heating of the S-atoms enhances this disorder. The increasing disorder of H-SAM chains with time results from both disorder at the Au/S interface and heat transfer to the H-SAM chains.

Energy transfer, unfolding, and fragmentation dynamics in collisions of N-protonated octaglycine with an H-SAM surface.

Results are reported for PM3 and RM1 QM+MM direct dynamics simulations of collisions of N-protonated octaglycine (gly(8)-H(+)) with an octanethiol self-assembled monolayer (H-SAM) surface. Detailed analyses of the energy transfer, fragmentation, and conformational changes induced by the collisions are described. Extensive comparisons are made between the simulations and previously reported experimental studies. Good agreement between the two semiempirical methods is found regarding energy transfer, while differences are seen for their fragmentation time scales. Trajectories were calculated for 8 ps with collision energies from 5 to 110 eV and incident angles of 0 degrees and 45 degrees. A linear relationship is found between the collision energy and key parameters of the final internal energy distributions of both gly(8)-H(+) and the H-SAM. In general wider distributions are seen for the H-SAM than for the peptide ion. An incident angle of 45 degrees leads to more energy transfer to the peptide, with wider distributions. The average percentage energy transfer to gly(8)-H(+) is nearly independent of the collision energy, while the average percentage transfer to the surface increases with collision energy. For normal incidence, we find an average percentage energy transfer to gly(8)-H(+) which is in excellent agreement with the experimentally measured value 10.1 +/- 0.8% for the octapeptide des-Arg(1)-bradykinin [J. Chem. Phys. 2003, 119, 3414]. At each collision energy dramatic conformational changes of gly(8)-H(+) are seen. The initial folded structure rearranges to form a beta-sheet like structure showing that the collision induces peptide unfolding. This process is more pronounced at an incident angle of 45 degrees. Following the conformation change, nonshattering fragmentation, promoted by proton transfer, is observed at the highest collision energies. Substantially more fragmentation occurs for the RM1 simulations.

NH4(+) + CH4 gas phase collisions as a possible analogue to protonated peptide/surface induced dissociation.

Results are reported for a direct dynamics simulation of NH(4)(+) + CH(4) gas phase collisions. We interpret the results with protonated peptide/hydrogenated alkanethiolate self-assembled monolayer (H-SAM) surface collisions in mind. Previous theoretical studies of such systems have made use of nonreactive surfaces, and therefore, our goal is to investigate the types and likelihood of peptide/H-SAM reactions. In that vein, the NH(4)(+) + CH(4) reaction represents a simple gas phase system which includes many of the important interactions present in protonated peptide/H-SAM surfaces. Thirty-seven open pathways are seen in the 5-35 eV collision energy range. An energy dependence on the likelihood of forming CN bonds is found. This type of bonding could deposit both the peptide and its molecular fragments on the H-SAM surface. For our gas phase collision system, around 50% of the trajectories result in the formation of CN bonds. For all collision energies in which reactive scattering occurs, CN bond formation is an important reaction pathway.

Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function.

Non-invasive characterization of fracture callus structure and composition may facilitate development of surrogate measures of the regain of mechanical function. As such, quantitative computed tomography- (CT-) based analyses of fracture calluses could enable more reliable clinical assessments of bone healing. Although previous studies have used CT to quantify and predict fracture healing, it is unclear which of the many CT-derived metrics of callus structure and composition are the most predictive of callus mechanical properties. The goal of this study was to identify the changes in fracture callus structure and composition that occur over time and that are most closely related to the regain of mechanical function. Micro-computed tomography (microCT) imaging and torsion testing were performed on murine fracture calluses (n=188) at multiple post-fracture timepoints and under different experimental conditions that alter fracture healing. Total callus volume (TV), mineralized callus volume (BV), callus mineralized volume fraction (BV/TV), bone mineral content (BMC), tissue mineral density (TMD), standard deviation of mineral density (sigma(TMD)), effective polar moment of inertia (J(eff)), torsional strength, and torsional rigidity were quantified. Multivariate statistical analyses, including multivariate analysis of variance, principal components analysis, and stepwise regression were used to identify differences in callus structure and composition among experimental groups and to determine which of the microCT outcome measures were the strongest predictors of mechanical properties. Although calluses varied greatly in the absolute and relative amounts of mineralized tissue (BV, BMC, and BV/TV), differences among timepoints were most strongly associated with changes in tissue mineral density. Torsional strength and rigidity were dependent on mineral density as well as the amount of mineralized tissue: TMD, BV, and sigma(TMD) explained 62% of the variation in torsional strength (p<0.001); and TMD, BMC, BV/TV, and sigma(TMD) explained 70% of the variation in torsional rigidity (p<0.001). These results indicate that fracture callus mechanical properties can be predicted by several microCT-derived measures of callus structure and composition. These findings form the basis for developing non-invasive assessments of fracture healing and for identifying biological and biomechanical mechanisms that lead to impaired or enhanced healing.