Parallel replica dynamics simulation methods appropriate for the simulation of chemical reactions in molecular systems with many conformational degrees of freedom have been developed and applied to study the microsecond-scale pyrolysis of n-hexadecane in the temperature range of 2100-2500 K. The algorithm uses a transition detection scheme that is based on molecular topology, rather than energetic basins. This algorithm allows efficient parallelization of small systems even when using more processors than particles (in contrast to more traditional parallelization algorithms), and even when there are frequent conformational transitions (in contrast to previous implementations of the parallel replica algorithm). The parallel efficiency for pyrolysis initiation reactions was over 90% on 61 processors for this 50-atom system. The parallel replica dynamics technique results in reaction probabilities that are statistically indistinguishable from those obtained from direct molecular dynamics, under conditions where both are feasible, but allows simulations at temperatures as much as 1000 K lower than direct molecular dynamics simulations. The rate of initiation displayed Arrhenius behavior over the entire temperature range, with an activation energy and frequency factor of E(a) = 79.7 kcal/mol and log A/s(-1) = 14.8, respectively, in reasonable agreement with experiment and empirical kinetic models. Several interesting unimolecular reaction mechanisms were observed in simulations of the chain propagation reactions above 2000 K, which are not included in most coarse-grained kinetic models. More studies are needed in order to determine whether these mechanisms are experimentally relevant, or specific to the potential energy surface used.
Molecular dynamics simulations have been used to study the pyrolysis of eicosane (C2042 both in the gas phase and when confined to the interior of a (7,7) carbon nanotube. A reactive bond-order potential was used to model the thermal decomposition of covalent bonds. The unimolecular dissociation is first-order in both cases. The decomposition kinetics demonstrate Arrhenius temperature dependence, with similar activation barriers in both geometries. The decomposition rate is slower by approximately 30% in the confined system. This rate decrease is observed to be a result of recombination reactions due to collisions with the nanotube wall.
Methyl-lysine (Kme) recognition domains play a central role in epigenetic regulation during cellular differentiation, development, and gene transcription with more than 200 known “reader” domains in the human proteome. We describe our target-class approach to ligand design and discovery for three cancer relevant members of this large family: L3MBTL3 (a Malignant Brain Tumor (MBT) domain containing reader), 53BP1 (a tandem Tudor domain) and CBX7 (a chromo domain). The advantages of a small molecule driven approach to modulating chromatin biology are numerous: temporal resolution; mechanistic flexibility (targeting a specific activity of a protein as opposed to ablating them all with transgenic knock-outs or RNA-interference techniques); ease of delivery; and most significantly, when warranted, a small molecule tool has the potential to provide an immediate transition to a drug discovery effort, potentially cutting years off the time between target validation and therapeutic intervention. UNC1215 binds the MBT domains of L3MBTL3 with a Kd of 120 nM, competitively displacing mono- or dimethyl-lysine containing peptides. This probe is greater than 50-fold selective versus other members of the human MBT family and also demonstrates selectivity against more than 200 other Kme reader domains examined. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins and point mutants that disrupt the Kme binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215. The potency, specificity, and cellular effects of UNC1215 establish it as the first cell-active antagonist of a Kme reader domain and a useful chemical probe for biological studies of the function of L3MBTL3 (James, L. I. et al. Nat Chem Biol 2013, 9, 184-191). 53BP1 is a Kme binding protein that plays a central biological role in DNA Damage Repair (DDR) pathway via its recruitment to sites of DNA double strand breaks (DSB). BRCA1 is a checkpoint and DNA damage repair gene that is required for maintenance of genomic integrity, and the inheritance of mutated BRCA1 is a major risk factor for breast and ovarian cancer. The BRCA1 knockout murine model is embryonic lethal and a conditional knockout in mammary glands results in low frequency and long latency of mammary tumor formation. It was recently reported that the BRCA1-null developmental phenotype is rescued when placed on a 53BP1-null background. Adult mice from this model, that are null for both the 53BP1 and BRCA1 genes, age normally and display a very low incidence of tumor formation. Genomic instability can be rescued in 53BP1 knockouts because the homologous recombination (HR) pathway is largely restored in cells lacking both BRCA1 and 53BP1 (Cao, L. et al. Molecular cell 2009, 35 (4), 534-41). Based on this data, small molecule antagonists of 53BP1's biological function could act as viable therapeutics to restore HR in the DDR response in humans with BRAC1 mutations. We will report the first small molecule, fragment-like ligands with selectivity for binding to 53BP1. CBX7 is a chromo domain containing Kme reader that, along with other CBX domains, recruits the PRC1 complex to histone 3, lysine 27 trimethylation sites (H3K27me3) and enables transcriptional silencing downstream of the PRC2 complex which ‘writes’ the H3K27me3 mark via the catalytic activity of EZH2. As EZH2 is a well validated drug target with inhibitors now entering the clinic for the treatment of various cancers, we hypothesize that antagonism of the PRC1 complex recognition of H3K27me3 will phenocopy and perhaps synergize with the activity of EZH2 inhibitors (Konze, K. D. et al. ACS Chemical Biology 2013, 8, 1324-1334). Progress towards a chemical probe to validate CBX7 as a therapeutic target will be presented. The pursuit of high quality chemical probes for KMe reader proteins represents an emerging area that will open new avenues of research in chromatin biology and may in time, translate to new therapeutic approaches. Antagonists of the readers of acetylated lysine (BRD4 bromo domains) derived from pioneering chemical probe efforts (Filippakopoulos, P. et al. Nature 468, 1067-73 (2010)) have recently entered the clinic for the treatment of various malignancies and we hope that our chemical probe work will help to validate Kme readers as novel and significant anti-tumor targets. Citation Format: Lindsey I. James, Jake I. Stuckey, Brandi M. Baughman, Michael T. Perfetti, Samantha G. Pattenden, Brad M. Dickson, Jacqueline L. Norris, Gaofeng Cui, Pavel Mader, Aiping Dong, Yunxiang Mu, Scott B. Rothbart, Brian D. Strahl, Jinrong Min, Peter J. Brown, Dmitri B. Kireev, William P. Janzen, Kevin M. McBride, Mark T. Bedford, Georges Mer, Cheryl H. Arrowsmith, Stephen V. Frye. Targeting chromatin regulation for cancer therapy: progress towards chemical probes for methyl-lysine readers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY08-03. doi:10.1158/1538-7445.AM2015-SY08-03
Molecular dynamics simulations of ethylene polymerization have been performed using a chemically realistic, reactive potential. These simulations have been performed in the bulk liquid and in the interior of both (10,10) and (7,7) nanotubes as a means of investigating the effects of nanoscale confinement on the polymerization reaction. The structure of the resulting polymer was found to be similar in the bulk and in the (10,10) tube at the elevated temperatures investigated, while only very small oligomers were formed in the (7,7) tube. The reaction rate was substantially reduced in the nanotubes, when compared to the bulk, primarily as a result of spatial interference due to reaction products. These simulations have implications for the possible use of nanotubes as synthetic reaction vessels, as well as for the general understanding of association reactions in confined spaces.
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