Simulating ion channel activation mechanisms using swarms of trajectories

Atomic-level studies of protein activity represent a significant challenge as a result of the complexity of conformational changes occurring on wide-ranging timescales, often greatly exceeding that of even the longest simulations. A prime example is the elucidation of protein allosteric mechanisms, where localized perturbations transmit throughout a large macromolecule to generate a response signal. For example, the conversion of chemical to electrical signals during synaptic neurotransmission in the brain is achieved by specialized membrane proteins called pentameric ligand-gated ion channels. Here, the binding of a neurotransmitter results in a global conformational change to open an ion-conducting pore across the nerve cell membrane. X-ray crystallography has produced static structures of the open and closed states of the proton-gated GLIC pentameric ligand-gated ion channel protein, allowing for atomistic simulations that can uncover changes related to activation. We discuss a range of enhanced sampling approaches that could be used to explore activation mechanisms. In particular, we describe recent application of an atomistic string method, based on Roux's “swarms of trajectories” approach, to elucidate the sequence and interdependence of conformational changes during activation. We illustrate how this can be combined with transition analysis and Brownian dynamics to extract thermodynamic and kinetic information, leading to understanding of what controls ion channel function. © 2019 Wiley Periodicals, Inc.     

Chemical promenades: Exploring potential-energy surfaces with immersive virtual reality

The virtual-reality framework AVATAR (Advanced Virtual Approach to Topological Analysis of Reactivity) for the immersive exploration of potential-energy landscapes is presented. AVATAR is based on modern consumer-grade virtual-reality technology and builds on two key concepts: (a) the reduction of the dimensionality of the potential-energy surface to two process-tailored, physically meaningful generalized coordinates, and (b) the analogy between the evolution of a chemical process and a pathway through valleys (potential wells) and mountain passes (saddle points) of the associated potential energy landscape. Examples including the discovery of competitive reaction paths in simple A + BC collisional systems and the interconversion between conformers in ring-puckering motions of flexible rings highlight the innovation potential that augmented and virtual reality convey for teaching, training, and supporting research in chemistry.     

Oversampling Free Energy Perturbation Simulation in Determination of the Ligand-Binding Free Energy

Determination of the ligand-binding affinity is an extremely interesting problem. Normally, the free energy perturbation (FEP) method provides an appropriate result. However, it is of great interest to improve the accuracy and precision of this method. In this context, temperature replica exchange molecular dynamics implementation of the FEP computational approach, which we call replica exchange free energy perturbation (REP) was proposed. In particular, during REP simulations, the system can easily escape from being trapped in local minima by exchanging configurations with high temperatures, resulting in significant improvement in the accuracy and precision of protein–ligand binding affinity calculations. The distribution of the decoupling free energy was enlarged, and its mean values were decreased. This results in changes in the magnitude of the calculated binding free energies as well as in alteration in the binding mechanism. Moreover, the REP correlation coefficient with respect to experiment ( R^REP = 0.85 ± 0.15 ) is significantly boosted in comparison with the FEP one ( R^FEP = 0.64 ± 0.30 ). Furthermore, the root-mean-square error (RMSE) of REP is also smaller than FEP, RMSE^REP = 4.28 ± 0.69 versus RMSE^FEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc.     

Anisotropic charge carrier transport of optoelectronic functional selenium-containing organic semiconductor materials

Organic semiconductors (OSCs) materials are currently under intense investigation because of their potential applications such as organic field-effect transistors, organic photovoltaic devices, and organic light-emitting diodes. Inspired by the selenization strategy can promote anisotropic charge carrier migration, and selenium-containing compounds have been proved to be promising materials as OSCs both for hole and electron transfer. Herein, we now explore the anisotropic transport properties of the series of selenium-containing compounds. For the compound containing Se Se bond, the Se Se bond will break when attaching an electron, thus those compounds cannot act as n-type OSCs. About the different isomer compounds with conjugated structure, the charge transfer will be affected by the stacking of the conjugated structures. The analysis of chemical structure and charge transfer property indicates that Se-containing materials are promising high-performance OSCs and might be used as p-type, n-type, or ambipolar OSCs. Furthermore, the symmetry of the selenium-containing OSCs will affect the type of OSCs. In addition, there is no direct relationship between the R groups with their performance, whether it or not as p-type OSCs or n-types. This work demonstrates the relationship between the optoelectronic function and structure of selenium-containing OSCs materials and hence paves the way to design and improve optoelectronic function of OSCs materials.     

Quantitative decomposition of resonance-assisted hydrogen bond energy in β-diketones into resonance and hydrogen bonding (π- and σ-) components using molecular tailoring and function-based approaches

Using the molecular tailoring and function-based approaches allows one to divide the energy of the O─H⋯O═C resonance-assisted hydrogen bond in a series of the β-diketones into resonance and hydrogen bonding components. The magnitude of the resonance component is assessed as about 6 kcal mol⁻¹. This value increases by ca. 1 kcal mol⁻¹ on going from the weak to strong resonance-assisted hydrogen bonding. The magnitude of the hydrogen bonding component varies in the wide range from 2 to 20 kcal mol⁻¹ depending on the structure of the β-diketone in question.     

Conformational and electronic study of dopamine interacting with the D2 dopamine receptor

We report an exhaustive conformational and electronic study on dopamine (DA) interacting with the D₂ dopamine receptor (D₂DR). For the first time, the complete surface of the conformational potential energy of the complex DA/D₂DR is reported. Such a surface was obtained through the use of QM/MM calculations. A detailed study of the molecular interactions that stabilize and destabilize the different molecular complexes was carried out using two techniques: Quantum Theory of Atoms in Molecules computations and nuclear magnetic shielding constants calculations. A comparative study of the behavior of DA in the gas phase, aqueous solution, and in the active site of D₂DR has allowed us to evaluate the degree of deformation suffered by the ligand and, therefore, analyze how rustic are the lock-key model and the induced fit theory in this case. Our results allow us to propose one of the conformations obtained as the “biologically relevant” conformation of DA when it is interacting with the D₂DR.     

线性响应和两种态特定方法模拟AF350电子跃迁的溶剂效应

在极化连续模型框架下比较了线性响应与两种不同态特定方法计算的溶液中Alexa Fluor 350(AF350)分子激发能和光谱移动值的差异. AF350的第一激发态S0→S1电子跃迁属于π→π^*跃迁, 主要对应于最高占据分子轨道(HOMO)到最低空轨道(LUMO)的跃迁. 该分子激发态偶极矩大于基态偶极矩, 激发态时溶质溶剂相互作用比基态时更强, 随着溶剂极性增大, 会发生光谱红移的现象. 与实验值相比, 线性响应和两种态特定方法均高估了激发能, 其中以IBSF(Improta-Barone-Scalmani-Frisch)方法得到的激发能最小, 矫正的基态反应场方法(cGSRF)得到的激发能最大. 对于光谱移动值, 3种方法与实验值相比都偏小, 线性响应方法(LR)计算出的误差最大, 而IBSF方法得到的结果与实验值最吻合, 是预测溶液中AF350分子激发能和光谱移动值最准确的方法. 对比了Marcus传统理论和基于约束平衡的非平衡溶剂化理论的结果, 发现后者得到的激发能和光谱移动值更接近于实验值.     

A density functional theory-time-dependent density functional theory investigation of photo-induced hydrogen bond and proton transfer for 2-(3,5-dichloro-2,6-dihydroxy-phenyl)-benzoxazole-6-carboxylicacid

Given the paramount importance of excited-state relaxation in the photochemical process, excited-state hydrogen bonding interactions and excited-state intramolecular proton transfer (ESIPT) are always hot topics. In this work, we theoretically explore the excited-state dynamical behaviors for a novel 2-(3,5-dichloro-2,6-dihydroxy-phenyl)-benzoxazole-6-carboxylicacid (DDPBC) system. As two intramolecular hydrogen bonds (O1 H2⋯N3 and O4 H5⋯O6) exist in the DDPBC structure, we first check if the double proton transfer form cannot be formed in the S1 state. Then, we explore the changes of geometrical parameters involved in hydrogen bonds, based on which we confirm that the dual intramolecular hydrogen bonds are strengthened on photo-excitation. The O1 H2⋯N3 hydrogen bond particularly plays a more important role in excited state. When it comes to the photo-induced excitation, we find charge transfer and electronic density redistribution around O1 H2 and N3 atom moieties. We verify the ESIPT tendency arising from the O1 H2⋯N3 hydrogen bond. In the analysis of the potential energy curves, along with O1 H2⋯N3 and O4 H5⋯O6, we demonstrate that the ESIPT reaction should occur along with O1 H2⋯N3 rather than O4 H5⋯O6. This work not only clarifies the specific ESIPT mechanism for DDPBC system but also paves the way for further novel applications based on DDPBC structure in the future.     

Hammett and Brown correlations in the structure and electronic properties of H2Si=SiHAr (Ar = p-C6H4X; X = NH2, OH,Me, H,F, Cl,CHO, COOH,CN, NO2) molecules

Substituent effect on the structure and electronic properties of H₂Si=SiHAr (Ar = p-C₆H₄X; X = NH₂, OH, Me, H, F, Cl, CHO, COOH, CN, NO₂) molecules are studied at the CAM-B3LYP/6-311G(d,p) level of theory. Energy decomposition analysis (EDA) is used as a useful tool for illustrating the interaction between H₂Si and SiHAr fragments in HArSi=SiH₂ molecules. Energetic analysis reveals that the singlet state of the fragments is more stable than triplet state. Also, interactions are stronger in the presence of electron-withdrawing groups (EWGs) in comparison to electron donating groups (EDGs). EDG and EDG effects are investigated on the stability of fragments, frontier orbital energy, distortion, HOMO–LUMO gap, electron-donating (ω⁻) and electron-accepting (ω⁺) powers of the studied molecules. Then, the correlations between these calculated parameters with the Hammett and Brown constants (σ_p and σ_p⁺, respectively) are provided. Also, time-dependent density functional theory method (TD-DFT) is employed for the determination of the strongest absorption band values (λ_max,el) of these molecules. This absorption band is attributed to the HOMO →LUMO transition.