Analysis of volatile components in inkjet printouts by GC-MS: A classification method.

Considering the high use of inkjet printing in forgery cases, the classification of inkjet printing is particularly important in questioned document examination. In this work, a universal GC-MS method has been developed to analyze various ink components extracted from inkjet printouts. The results indicated that several components detected and identified across 195 inks could be used to distinguish printer manufacturers. A trend of decreasing solvent concentration over time was observed through the continuous monitoring of 7 samples. The results shown that this method is useful for forensic classification purposes, and can be useful regardless effects of storage environment, paper or printer. Furthermore, the application of this method in the analysis of counterfeit banknotes illustrated its feasibility and applicability.

Mutation-mediated influences on binding of anaplastic lymphoma kinase to crizotinib decoded by multiple replica Gaussian accelerated molecular dynamics.

Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In the current work, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations, molecular mechanics generalized Born surface area (MM-GBSA) and free energy landscapes were coupled to explore influences of mutations L1198F, L1198F/C1156Y, and C1156Y on the binding of the first ALK inhibitor crizotinib to ALK. The results suggest that three mutations obviously affect structural flexibility, motion modes and conformational changes of ALKs. L1198F and L1198F/C1156Y strengthen the binding of crizotinib to the mutated ALKs but C1156Y induces evident drug resistance toward crizotinib. Analyses of free energy landscapes show that stability in the orientation and positions of crizotinib relative to ALK plays a vital role in alleviating drug resistance of mutations toward crizotinib. Residue-based free energy decomposition method was utilized to evaluate the contributions of separate residues to the binding of crizotinib. The results not only indicate that the tuning of point mutation L1198F on interaction networks of crizotinib with ALK can be regarded as a possible strategy to relieve drug resistance of the mutated ALK but also further verify that residues L1122, V1130, L1196, L1198, M1199, and L1256 can be used as efficient targets of anti-drug resistance design induced by mutations.

Effects of Disulfide Bonds on Binding of Inhibitors to ß-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations.

The ß-amyloid cleaving enzyme 1 (BACE1) has been thought to be an efficient target for treatment of Alzheimer's disease (AD). Deep insight into inhibitor-BACE1 binding mechanism is of significance for design of potent drugs toward BACE1. In this work, multiple replica accelerated molecular dynamics (MR-aMD) simulations, principal component (PC) analysis, and free energy landscapes were integrated to decode the effect of disulfide bonds (SSBs) in BACE1 on bindings of three inhibitors 3KO, 3KT, and 779 to BACE1. The results from cross-correlation analysis suggest that the breaking of SSBs exerts significant influence on structural flexibility and internal dynamics of inhibitor-bound BACE1. PC analysis and free energy landscapes reveal that the breaking of SSBs not only evidently induces the conformational rearrangement of BACE1 but also highly changes binding poses of three inhibitors in BACE1 and leads to more disordered binding of three inhibitors to BACE1, which is further supported by the increase in binding entropy of inhibitors to BACE1 due to the breaking of SSBs. Residue-based free energy decomposition method was utilized to evaluate contributions of separate residues to inhibitor-BACE1 binding. The results suggest that although the breaking of SSBs in BACE1 does not destroy the interaction network of inhibitors with BACE1 it changes interaction strength of some residues with inhibitors. Meanwhile, the information from residue-based free energy decomposition indicates that residues L91, S96, V130, Y132, Q134, W137, F169, I171, and I179 can be used as efficient targets of drug design toward BACE1.

Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies.

The FK506-binding protein 51 (FKBP51) is a cochaperone that modulates the signal transduction of steroid hormone receptors and has been involved in prostate cancer, indicating that FKBP51 is an attractive target of drug design curing the related cancers. In this work, multiple short molecular dynamics (MSMD) simulations are combined with MM-GBSA method to investigate binding modes of inhibitors 3JP, 3JR and 3JQ to FKBP51. The results show that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP strengthen binding of 3JR and 3JQ to FKBP51. Principal component (PC) analysis performed on the equilibrated MSMD trajectories suggests that three inhibitor bindings produce significant effect on dynamics behavior and conformational changes of the loops L1, L2 and the domain ß-L-α-L-ß in FKBP51. The calculations of residue-based free energy decomposition not only recognize the hot interaction spot of inhibitors with FKBP51, but also display that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP play significant role in stronger binding of 3JR and 3JQ to FKBP51 than 3JP. This work is expected to provide theoretical hints and molecular mechanism for design of highly efficient inhibitors toward FKBP51.

Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions.

The ß-amyloid cleaving enzymes 1 and 2 (BACE1 and BACE2) have been regarded as the prospective targets for clinically treating Alzheimer's disease (AD) in the last two decades. Thus, insight into the binding differences of inhibitors to BACE1 and BACE2 is of significance for designing highly selective inhibitors toward the two proteins. In this work, multiple short molecular dynamics (MSMD) simulations are coupled with the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding selectivity of three inhibitors DBO, CS9, and SC7 on BACE1 over BACE2. The results show that the entropy effect plays a key role in selectivity identification of inhibitors toward BACE1 and BACE2, which determines that DBO has better selectivity toward BACE2 over BACE1, while CS9 and CS7 can more favorably bind to BACE1 than BACE2. The hierarchical clustering analysis based on energetic contributions of residues suggests that BACE1 and BACE2 share the common hot interaction spots. The residue-based free-energy decomposition method was applied to compute the inhibitor-residue interaction spectrum, and the results recognize four common binding subpockets corresponding to the different groups of inhibitors, which can be used as efficient targets for designing highly selective inhibitors toward BACE1 and BACE2. Therefore, these results provide a useful molecular basis and dynamics information for development of highly selective inhibitors targeting BACE1 and BACE2.

Dynamical fluxionality, multiplicity of structural forms, and electronic properties of the B3Si11 cluster: anion photoelectron spectroscopy and theoretical calculations.

The geometrical structures and electronic properties of anionic, neutral, and cationic B3Si11 clusters were investigated by performing ab initio calculations combined with size-selected anion photoelectron spectroscopy. The experimental photoelectron spectrum of the B3Si11- anion is reasonably reproduced by theoretical simulations of two competing isomers. The global minimum of the B3Si11- anion is formed by the fusion of a B3Si7 bicapped tetragonal antiprism to a B3Si4 pentagonal bipyramid by sharing a B3 triangle, while that of neutral B3Si11 has a B3-endohedral sandwich structure composed of a Si5 five-membered ring and a Si6 six-membered ring, and that of the B3Si11+ cation adopts a Si11 tricapped tetragonal antiprism with three face-capping B atoms. It is interesting that a Si5 five-membered ring and a Si6 six-membered ring are stabilized by three B atoms in B3Si11. The three B atoms tend to bond with each other to form a B3 triangle with stronger B-B bonds than B-Si bonds. Moreover, neutral B3Si11 exhibits σ + π double delocalized bonding patterns. Anionic, neutral, and cationic B3Si11 clusters have multiplicity of structural forms and their low-lying isomers show dynamical fluxionality. The bond lengths, bond orders, MO, constant electronic charge density surfaces, and PDOS analyses showed that the three B atoms in B3Si11 have strong bonding interactions.

Forensic classification of counterfeit banknote paper by X-ray fluorescence and multivariate statistical methods.

Counterfeiting of banknotes is a crime and seriously harmful to economy. Examination of the paper, ink and toners used to make counterfeit banknotes can provide useful information to classify and link different cases in which the suspects use the same raw materials. In this paper, 21 paper samples of counterfeit banknotes seized from 13 cases were analyzed by wavelength dispersive X-ray fluorescence. After measuring the elemental composition in paper semi-quantitatively, the normalized weight percentage data of 10 elements were processed by multivariate statistical methods of cluster analysis and principle component analysis. All these paper samples were mainly classified into 3 groups. Nine separate cases were successfully linked. It is demonstrated that elemental composition measured by XRF is a useful way to compare and classify papers used in different cases.