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1.
J Chem Phys ; 152(10): 104108, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171226

RESUMO

Markov processes are widely used models for investigating kinetic networks. Here, we collate and present a variety of results pertaining to kinetic network models in a unified framework. The aim is to lay out explicit links between several important quantities commonly studied in the field, including mean first passage times (MFPTs), correlation functions, and the Kemeny constant. We provide new insights into (i) a simple physical interpretation of the Kemeny constant, (ii) a relationship to infer equilibrium distributions and rate matrices from measurements of MFPTs, and (iii) a protocol to reduce the dimensionality of kinetic networks based on specific requirements that the MFPTs in the coarse-grained system should satisfy. We prove that this protocol coincides with the one proposed by Hummer and Szabo [J. Phys. Chem. B 119, 9029 (2014)], and it leads to a variational principle for the Kemeny constant. Finally, we introduce a modification of this protocol, which preserves the Kemeny constant. Our work underpinning the theoretical aspects of kinetic networks will be useful in applications including milestoning and path sampling algorithms in molecular simulations.

2.
J Chem Theory Comput ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32097548

RESUMO

We present here two irreversible Markov chain Monte Carlo algorithms for general discrete state systems. One of the algorithms is based on the random-scan Gibbs sampler for discrete states and the other on its improved version, the Metropolized-Gibbs sampler. The algorithms we present incorporate the lifting framework with skewed detailed balance condition and construct irreversible Markov chains that satisfy the balance condition. We have applied our algorithms to 1D 4-state Potts model. The integrated autocorrelation times for magnetization and energy density indicate a reduction of the dynamical scaling exponent from z ≈ 1 to z ≈ 1/2. In addition, we have generalized an irreversible Metropolis-Hastings algorithm with skewed detailed balance, initially introduced by Turitsyn et al. [ Physica D 2011, 240, 410] for the mean field Ising model, to be now readily applicable to classical spin systems in general; application to 1D 4-state Potts model indicate a square root reduction of the mixing time at high temperatures.

3.
Science ; 367(6479): 806-810, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32001525

RESUMO

Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.


Assuntos
Farmacorresistência Viral , Inibidores de Integrase de HIV/química , Integrase de HIV/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Substituição de Aminoácidos/genética , Domínio Catalítico , Microscopia Crioeletrônica/métodos , Glutamina/genética , Glicina/genética , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Histidina/genética , Humanos , Magnésio/química , Mutação , Serina/genética , Imagem Individual de Molécula/métodos
4.
Curr Opin Struct Biol ; 61: 198-206, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32065923

RESUMO

Here we discuss current trends in the simulations of enzymatic reactions focusing on phosphate catalysis. The mechanistic details of the proton transfers coupled to the phosphate cleavage is one of the key challenges in QM/MM calculations of these and other enzyme catalyzed reactions. The lack of experimental information offers both an opportunity for computations as well as often unresolved controversies. We discuss the example of small GTPases including the important human Ras protein. The high dimensionality and chemical complexity of these reactions demand carefully chosen computational techniques both in terms of the underlying quantum chemical theory and the sampling of the conformational ensemble. We also point out the important role of Mg2+ ions, and recent advances in their transient involvement in the catalytic mechanisms.

5.
J Am Chem Soc ; 142(3): 1382-1393, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31820966

RESUMO

In this study, we have developed a highly enantioselective organocatalytic route to the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a cis-configuration between the C- and N-termini around the cyclopentane core. Kinetic measurements show that the product distribution changes over time due to epimerization of the C1 center. Computations suggest the cis-selectivity is a result of selective C-C bond formation, while subsequent steps appear to influence the selectivity at higher temperature. The resulting γ-amino acid residue was incorporated into a novel γ/α-peptide, which forms a well-ordered 10/12-helix with alternate H-bond directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this type. This highly defined structure is also a result of the narrow range of potential ζ-angles in our monomer. In contrast, the larger range of potential ζ-values observed for the corresponding trans-system can be fulfilled by several competing helical structures.

6.
J Phys Chem Lett ; 11(1): 206-209, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31846339

RESUMO

We study the photodissociation induced by ultraviolet excitation of amide bonds in gas-phase protonated peptides. Jointly, mass spectrometry and cold ion spectroscopy provide evidence for a selective nonstatistical dissociation of specific peptide bonds in the spectral region of the formally forbidden n → π* transition of amide groups. Structural analysis reveals that the activation of this transition, peaked at 226 nm, originates from the nonplanar geometry of the bond. In contrast, the statistical dissociation in the electronic ground state appears to be the main outcome of the π → π* excitation of the peptide bonds at 193 nm. We propose a tentative model that explains the difference in the fragmentation mechanisms by the difference in localization of the electronic transitions and the higher amount of vibrational energy released in the electronic excited state upon absorption at 193 nm.

7.
Chem Sci ; 10(38): 8806-8811, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31803453

RESUMO

Cucurbit[8]uril (CB[8]) mediated assembly of extended aryl viologens (EVs) into optically tunable dimers is reported for the first time. We show that the modular design and synthesis of a new class of π-conjugated viologen derivatives with rigid aromatic or heteroaromatic bridging units as well as electron donating molecular recognition motifs enable their self-assembly into 2 : 2 complexes with CB[8]. The quantitative dimerization process involving these two molecular components in an aqueous solution enables excimer-like interactions between closely packed charged guests giving rise to distinct spectroscopic behavior. The nature of these dimers (CB[8]2·(EV[X]R)2) in the ground and excited states was characterized by NMR, isothermal titration calorimetry, and steady-state spectroscopic measurements.

8.
J Chem Phys ; 151(19): 190401, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31757166
9.
Phys Chem Chem Phys ; 21(41): 22700-22703, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31579899

RESUMO

We use cold ion spectroscopy and quantum-chemical computations to solve the structures of opioid peptides enkephalins in the gas phase. The derived structural parameters clearly correlate with the known pharmacological efficiency of the studied drugs, suggesting that gas-phase methods, perhaps, can be used for predicting the relative potency of ligand drugs that target the hydrophobic pockets of receptors.


Assuntos
Encefalinas/química , Gases/química , Modelos Moleculares , Análise Espectral , Encefalinas/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neurotransmissores/química , Neurotransmissores/farmacologia , Relação Estrutura-Atividade
10.
ACS Sens ; 4(11): 2988-2996, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31565921

RESUMO

Quantitative applications of surface-enhanced Raman spectroscopy (SERS) often rely on surface partition layers grafted to SERS substrates to collect and trap-solvated analytes that would not otherwise adsorb onto metals. Such binding layers drastically broaden the scope of analytes that can be probed. However, excess binding sites introduced by this partition layer also trap analytes outside the plasmonic "hotspots". We show that by eliminating these binding sites, limits of detection (LODs) can effectively be lowered by more than an order of magnitude. We highlight the effectiveness of this approach by demonstrating quantitative detection of controlled drugs down to subnanomolar concentrations in aqueous media. Such LODs are low enough to screen, for example, urine at clinically relevant levels. These findings provide unique insights into the binding behavior of analytes, which are essential when designing high-performance SERS substrates.

11.
Chem Commun (Camb) ; 55(88): 13227-13230, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31631210

RESUMO

Pseudo[2,3]rotaxanes have been successfully fabricated by the complexation of cucurbit[8]uril (CB[8]) macrocycles with extended viologen derivatives. Two design rules enable the incorporation of a third CB[8] onto a recently reported pseudo[2,2]rotaxane. Incorporation of a third macrocycle confines the dimeric stacking of chromophores into specific alignment, leading to effective electron-delocalisation along their long molecular axis.

12.
J Chem Phys ; 150(13): 134107, 2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30954057

RESUMO

Markov state models (MSMs) provide some of the simplest mathematical and physical descriptions of dynamical and thermodynamical properties of complex systems. However, typically, the large dimensionality of biological systems studied makes them prohibitively expensive to work in fully Markovian regimes. In this case, coarse graining can be introduced to capture the key dynamical processes-slow degrees of the system-and reduce the dimension of the problem. Here, we introduce several possible options for such Markovian coarse graining, including previously commonly used choices: the local equilibrium and the Hummer Szabo approaches. We prove that the coarse grained lower dimensional MSM satisfies a variational principle with respect to its slowest relaxation time scale. This provides an excellent framework for optimal coarse graining, as previously demonstrated. Here, we show that such optimal coarse graining to two or three states has a simple physical interpretation in terms of mean first passage times and fluxes between the coarse grained states. The results are verified numerically using both analytic test potentials and data from explicit solvent molecular dynamics simulations of pentalanine. This approach of optimizing and interpreting clustering protocols has broad applicability and can be used in time series analysis of large data.

13.
Nano Lett ; 19(3): 2051-2058, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30726095

RESUMO

The resonance wavelength of a coupled plasmonic system is extremely sensitive to the distance between its metallic surfaces, resulting in "plasmon rulers". We explore this behavior in the subnanometer regime using self-assembled monolayers of bis-phthalocyanine molecules in a nanoparticle-on-mirror (NPoM) construct. These allow unprecedented subangstrom control over spacer thickness via choice of metal center, in a gap-size regime at the quantum-mechanical limit of plasmonic enhancement. A dramatic shift in the coupled plasmon resonance is observed as the gap size is varied from 0.39 to 0.41 nm. Existing theoretical models are unable to account for the observed spectral tuning, which requires inclusion of the quantum-classical interface, emphasizing the need for new treatments of light at the subnanoscale.

14.
J Phys Chem Lett ; 9(24): 7146-7151, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30525662

RESUMO

Reproducible confinement of light on the nanoscale is essential for the ability to observe and control chemical reactions at the single-molecule level. Here we reliably form millions of identical nanocavities and show that the light can be further focused down to the subnanometer scale via the creation of picocavities, single-adatom protrusions with angstrom-level resolution. For the first time, we stabilize and analyze these cavities at room temperatures through high-speed surface-enhanced Raman spectroscopy on specifically selected molecular components, collecting and analyzing more than 2 million spectra. Data obtained on these picocavities allows us to deduce structural information on the nanoscale, showing that thiol binding to gold destabilizes the metal surface to optical irradiation. Nitrile moieties are found to stabilize picocavities by 10-fold against their disappearance, typically surviving for >1 s. Such constructs demonstrate the accessibility of single-molecule chemistry under ambient conditions.

15.
Molecules ; 23(10)2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30274290

RESUMO

In QM/MM calculations, it is essential to handle electrostatic interactions between the QM and MM subsystems accurately and efficiently. To achieve maximal efficiency, it is convenient to adopt a hybrid scheme, where the QM electron density is used explicitly in the evaluation of short-range QM/MM electrostatic interactions, while a multipolar representation for the QM electron density is employed to account for the long-range QM/MM electrostatic interactions. In order to avoid energy discontinuity at the cutoffs, which separate the short- and long-range QM/MM electrostatic interactions, a switching function should be utilized to ensure a smooth potential energy surface. In this study, we benchmarked the accuracy of such hybrid embedding schemes for QM/MM electrostatic interactions using different multipolar representations, switching functions and cutoff distances. For test systems (neutral and anionic oxyluciferin in MM (aqueous and enzyme) environments), the best accuracy was acquired with a combination of QM electrostatic potential (ESP) charges and dipoles and two switching functions (long-range electrostatic corrections (LREC) and Switch) in the treatment of long-range QM/MM electrostatics. It allowed us to apply a 10Å distance cutoff and still obtain QM/MM electrostatics/polarization energies within 0.1 kcal/mol and time-dependent density functional theory (TDDFT)/MM vertical excitation energies within 10-3 eV from theoretical reference values.


Assuntos
Modelos Moleculares , Simulação por Computador , Elétrons , Indóis/química , Luciferases de Vaga-Lume/química , Estrutura Molecular , Pirazinas/química , Teoria Quântica , Eletricidade Estática , Termodinâmica , Fatores de Tempo , Água/química
16.
J Phys Chem B ; 122(49): 11571-11578, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30247032

RESUMO

We present a simple approach to calculate the kinetic properties of lipid membrane crossing processes from biased molecular dynamics simulations. We demonstrate that by using biased simulations, one can obtain highly accurate kinetic information with significantly reduced computational time with respect to unbiased simulations. We describe how to conveniently calculate the transition rates to enter, cross, and exit the membrane in terms of the mean first passage times. To obtain free energy barriers and relaxation times from biased simulations only, we constructed Markov models using the dynamic histogram analysis method (DHAM). The permeability coefficients that are calculated from the relaxation times are found to correlate highly with experimentally evaluated values. We show that more generally, certain calculated kinetic properties linked to the crossing of the membrane layer (e.g., barrier height and barrier crossing rates) are good indicators of ordering drugs by permeability. Extending the analysis to a 2D Markov model provides a physical description of the membrane crossing mechanism.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Simulação de Dinâmica Molecular , Clorpromazina/química , Clorpromazina/farmacologia , Desipramina/química , Desipramina/farmacologia , Domperidona/química , Domperidona/farmacologia , Cinética , Labetalol/química , Labetalol/farmacologia , Bicamadas Lipídicas/química , Loperamida/química , Loperamida/farmacologia , Estrutura Molecular , Propranolol/química , Propranolol/farmacologia , Termodinâmica , Verapamil/química , Verapamil/farmacologia
17.
J Chem Phys ; 149(7): 072324, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134666

RESUMO

Markov state models (MSMs) are more and more widely used in the analysis of molecular simulations to incorporate multiple trajectories together and obtain more accurate time scale information of the slowest processes in the system. Typically, however, multiple lagtimes are used and analyzed as input parameters, yet convergence with respect to the choice of lagtime is not always possible. Here, we present a simple method for calculating the slowest relaxation time (RT) of the system in the limit of very long lagtimes. Our approach relies on the fact that the second eigenvector's autocorrelation function of the propagator will be approximately single exponential at long lagtimes. This allows us to obtain a simple equation for the behavior of the MSM's relaxation time as a function of the lagtime with only two free parameters, one of these being the RT of the system. We demonstrate that the second parameter is a useful indicator of how Markovian a selected variable is for building the MSM. Fitting this function to data gives a limiting value for the optimal variational RT. Testing this on analytic and molecular dynamics data for Ala5 and umbrella sampling-biased ion channel simulations shows that the function accurately describes the behavior of the RT and furthermore that this RT can improve noticeably the value calculated at the longest accessible lagtime. We compare our RT limit to the hidden Markov model (HMM) approach that typically finds RTs of comparable values. However, HMMs cannot be used in conjunction with biased simulation data, requiring more complex algorithms to construct than MSMs, and the derived RTs are not variational, leading to ambiguity in the choice of lagtime at which to build the HMM.

18.
Cell Syst ; 7(2): 161-179.e14, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30007540

RESUMO

Clinically used RAF inhibitors are ineffective in RAS mutant tumors because they enhance homo- and heterodimerization of RAF kinases, leading to paradoxical activation of ERK signaling. Overcoming enhanced RAF dimerization and the resulting resistance is a challenge for drug design. Combining multiple inhibitors could be more effective, but it is unclear how the best combinations can be chosen. We built a next-generation mechanistic dynamic model to analyze combinations of structurally different RAF inhibitors, which can efficiently suppress MEK/ERK signaling. This rule-based model of the RAS/ERK pathway integrates thermodynamics and kinetics of drug-protein interactions, structural elements, posttranslational modifications, and cell mutational status as model rules to predict RAF inhibitor combinations for inhibiting ERK activity in oncogenic RAS and/or BRAFV600E backgrounds. Predicted synergistic inhibition of ERK signaling was corroborated by experiments in mutant NRAS, HRAS, and BRAFV600E cells, and inhibition of oncogenic RAS signaling was associated with reduced cell proliferation and colony formation.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases raf/antagonistas & inibidores , Proteínas ras/metabolismo , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação/efeitos dos fármacos , Neoplasias/genética , Neoplasias/metabolismo , Multimerização Proteica/efeitos dos fármacos , Termodinâmica , Quinases raf/química , Quinases raf/metabolismo , Proteínas ras/genética
19.
J Biol Chem ; 293(25): 9724-9735, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29743239

RESUMO

The high-energy sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS), generated by human PAPS synthase isoforms PAPSS1 and PAPSS2, is required for all human sulfation pathways. Sulfotransferase SULT2A1 uses PAPS for sulfation of the androgen precursor dehydroepiandrosterone (DHEA), thereby reducing downstream activation of DHEA to active androgens. Human PAPSS2 mutations manifest with undetectable DHEA sulfate, androgen excess, and metabolic disease, suggesting that ubiquitous PAPSS1 cannot compensate for deficient PAPSS2 in supporting DHEA sulfation. In knockdown studies in human adrenocortical NCI-H295R1 cells, we found that PAPSS2, but not PAPSS1, is required for efficient DHEA sulfation. Specific APS kinase activity, the rate-limiting step in PAPS biosynthesis, did not differ between PAPSS1 and PAPSS2. Co-expression of cytoplasmic SULT2A1 with a cytoplasmic PAPSS2 variant supported DHEA sulfation more efficiently than co-expression with nuclear PAPSS2 or nuclear/cytosolic PAPSS1. Proximity ligation assays revealed protein-protein interactions between SULT2A1 and PAPSS2 and, to a lesser extent, PAPSS1. Molecular docking studies showed a putative binding site for SULT2A1 within the PAPSS2 APS kinase domain. Energy-dependent scoring of docking solutions identified the interaction as specific for the PAPSS2 and SULT2A1 isoforms. These findings elucidate the mechanistic basis for the selective requirement for PAPSS2 in human DHEA sulfation.


Assuntos
Carcinoma Adrenocortical/metabolismo , Sulfato de Desidroepiandrosterona/metabolismo , Complexos Multienzimáticos/metabolismo , Sulfato Adenililtransferase/metabolismo , Sulfotransferases/metabolismo , Sítios de Ligação , Núcleo Celular/metabolismo , Cristalografia por Raios X , Citosol/metabolismo , Sulfato de Desidroepiandrosterona/química , Humanos , Simulação de Acoplamento Molecular , Complexos Multienzimáticos/química , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Sulfato Adenililtransferase/química , Sulfotransferases/química , Células Tumorais Cultivadas
20.
Proc Natl Acad Sci U S A ; 114(48): E10339-E10348, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29133387

RESUMO

Proton pumping A-type cytochrome c oxidase (CcO) terminates the respiratory chains of mitochondria and many bacteria. Three possible proton transfer pathways (D, K, and H channels) have been identified based on structural, functional, and mutational data. Whereas the D channel provides the route for all pumped protons in bacterial A-type CcOs, studies of bovine mitochondrial CcO have led to suggestions that its H channel instead provides this route. Here, we have studied H-channel function by performing atomistic molecular dynamics simulations on the entire, as well as core, structure of bovine CcO in a lipid-solvent environment. The majority of residues in the H channel do not undergo large conformational fluctuations. Its upper and middle regions have adequate hydration and H-bonding residues to form potential proton-conducting channels, and Asp51 exhibits conformational fluctuations that have been observed crystallographically. In contrast, throughout the simulations, we do not observe transient water networks that could support proton transfer from the N phase toward heme a via neutral His413, regardless of a labile H bond between Ser382 and the hydroxyethylfarnesyl group of heme a In fact, the region around His413 only became sufficiently hydrated when His413 was fixed in its protonated imidazolium state, but its calculated pKa is too low for this to provide the means to create a proton transfer pathway. Our simulations show that the electric dipole moment of residues around heme a changes with the redox state, hence suggesting that the H channel could play a more general role as a dielectric well.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/fisiologia , Transporte de Elétrons/fisiologia , Heme/análogos & derivados , Transporte de Íons/fisiologia , Prótons , Animais , Transporte Biológico Ativo , Bovinos , Fenômenos Eletromagnéticos , Complexo IV da Cadeia de Transporte de Elétrons/química , Heme/química , Heme/fisiologia , Mitocôndrias/fisiologia , Simulação de Dinâmica Molecular , Água/química , Água/fisiologia
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