[Development of Membrane Permeability Coefficient by Means of Novel Molecular Dynamics Methods].

The membrane permeability, and its evaluation, is crucial factor in the process of uptake of compounds from outside to inside the cell and in the inhibition of the activity of disease-causing target proteins. Although molecular dynamics (MD) simulations have been shown to be able to reproduce the conformational changes of compounds occurring during membrane permeation, it is still challenging to extract the membrane permeability at an affordable computational workload solely by conventional MD. Indeed, the time scale accessible by MD is far below the one characterizing the actual permeation process. Phenomena occurring in living organisms escaping the reach of standard MD are generally referred to as biological rare events, and the membrane permeation process is one of them. To overcome this time-scale problem, several enhanced sampling methods have been proposed over the years to improve conformational sampling. In this review, a hybrid sampling method that combines the parallel cascade selection MD (PaCS-MD) and the outlier flooding method (OFLOOD), introduced and developed by our group, is proposed as a tool to study the membrane permeation from structural sampling (rare-event sampling). The obtained trajectories are used to estimate the free energy profiles for the membrane permeation and to compute the membrane permeation coefficients. Moreover, we present an example of application of the free energy reaction network method as a versatile way for incorporating explicitly into reaction coordinates the degrees of freedom related to internal motion.

Bilateral multiple stroke, left upper extremity ischemia, and transient complete atrioventricular block in transcatheter aortic valve implantation: a case report.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a minimally invasive surgery. However, there is a risk of surgical manipulation causing detachment of a lesion of the aortic valve, which can result in various embolisms. CASE PRESENTATION: An 87-year-old woman with symptomatic severe aortic valve stenosis was scheduled for transfemoral TAVI under monitored anesthesia. Preoperative examination revealed severe calcification of the aortic valve, but there was no calcification in the ascending aorta. After a delivery catheter system passed the aortic valve, left radial arterial pressure dropped significantly, and complete atrioventricular block (CAVB) occurred. Catecholamine administration and ventricular pacing improved hemodynamics, and a self-expandable valve was implanted. CAVB resolved after surgery, but her state of consciousness was poor, and her left hand became ischemic. Imaging studies revealed multiple embolic infarcts in her bilateral cerebrum and cerebellum. CONCLUSIONS: It should be noted that there is a risk of detachment of a calcified lesion of the aortic valve during TAVI, which can cause embolisms not only in the brain but also in the extremities and coronary arteries.

Anesthetic management with remimazolam in very elderly patients undergoing hybrid surgery of transcatheter aortic valve implantation plus off-pump coronary artery bypass grafting: report of two cases.

BACKGROUND: Remimazolam is a short-acting benzodiazepine with small circulatory depression. We used remimazolam for general anesthesia management in two very elderly patients undergoing hybrid surgery of transcatheter aortic valve implantation (TAVI) plus off-pump coronary artery bypass grafting (OPCABG). CASE PRESENTATION: A 96-year-old man (case 1) and a 92-year-old woman (case 2) had complex coronary artery disease (CAD) and severe aortic stenosis (AS) and were scheduled for TAVI plus OPCAB. Anesthesia in both patients was induced with 6 mg/kg/h remimazolam and fentanyl and maintained with 0.3 mg/kg/h and 0.5 mg/kg/h remimazolam and fentanyl, respectively. Although catecholamines were required, we successfully maintained circulation during the induction of anesthesia and the procedures of OPCAB and TAVI. Both patients were discharged without complications. CONCLUSION: Remimazolam can be a useful option for safe general anesthesia in very elderly patients when performing hybrid surgery.

Nudged elastic stiffness band method: A method to solve kinks problems of reaction paths.

The nudged elastic band (NEB) method has been widely employed for reaction path (RP) finding; however, certain NEB calculations do not converge to the minimum energy paths (MEPs) because of the occurrence of kinks, which are caused by the free bending of bands. Thus, we propose an extension of the NEB method, called the nudged elastic stiffness band (NESB) method, which adds the stress of stiffness using a beam theory. Here we present results from three examples: the NFK potential, the RPs of the Witting reaction, and finding saddle points for a set of five chemical reaction benchmarks. The results showed that the NESB method has three advantages: to decrease the number of iterations, shrink the length of the pathways from reducing unnecessary fluctuations, and find TS structures by converging to paths close to the MEPs for systems that have sharp curves on the MEPs.

Predictors of early postoperative cognitive dysfunction in middle-aged patients undergoing cardiac surgery: retrospective observational study.

PURPOSE: This study aimed to identify the incidence and risk factors of early post-operative cognitive dysfunction (POCD) in middle-aged patients undergoing cardiac surgery. METHODS: Data were examined retrospectively from 71 patients aged 46-64 years who underwent elective cardiac surgery. Magnetic resonance imaging (MRI) and MR angiography were obtained preoperatively to assess prior cerebral infarctions, carotid artery stenosis, and intracranial arterial stenosis. Patients also completed six neuropsychological tests of memory, attention, and executive function before and after surgery. Mild cognitive impairment (MCI) was defined as performance 1.5 standard deviations (SD) below the population means on any neurocognitive battery, whereas POCD was defined as a decrease of 1 SD population means on at least two in the test battery. Patient characteristics were analyzed using univariate analysis, and independent predictors were analyzed using multivariate logistic regression analysis. RESULTS: After surgery, 25 patients (35%) were assessed with POCD. Patients with POCD had significantly higher rates of preoperative MCI and cerebral infarcts on MRI. Multivariate logistic regression analysis identified preoperative MCI and cerebral infarctions detected by MRI as a predictor of POCD. CONCLUSION: More than one-third of middle-aged patients undergoing cardiac surgery developed POCD. Our findings suggested preoperative MCI and infarcts detected by MRI were risk factors for POCD in these middle-aged patients.

Curvature-weighted nudged elastic band method using the Riemann curvature.

The nudged elastic band (NEB) method is utilized to find reaction paths (RPs) using discretized intermediate structures called "images" between a reactant and a product. In fact, NEB calculations do not always converge because of the bent of RPs. Mathematically, more images are needed for complex curves, and here, we focused on the curvature. In this study, we propose a new method for calculating the curvature of the RPs as well as a method for weighting the spring constant of the NEB with the curvature, which we named the curvature weighted NEB (CW-NEB) method. In addition, we will propose the CW-NEB method with the climbing image (CI) method (CW-CI-NEB). To show the efficiency of our method, calculations for the ene-reaction of the CW-CI-NEB method were performed and compared with those of the CI-NEB methods. The CW-CI-NEB methods converged in shorter iteration times than the CI-NEB calculation, which was found by gathering the bent of RPs.

Calculation of the permeability coefficients of small molecules through lipid bilayers by free-energy reaction network analysis following the explicit treatment of the internal conformation of the solute.

Biomembrane permeation represents a major barrier to pharmacokinetics. During preclinical drug discovery, the coefficients of the permeation of molecules through lipid bilayers account for a valuable property of such molecules. Therefore, the control of the permeation of molecules through lipid bilayers is an essential factor in drug design, and the estimation of the permeation phenomena is a crucial study in pharmacy. Thus, there are many published studies on the theoretical estimations of permeation coefficients. Here, we propose a molecular dynamics (MD) simulation method for estimating the permeation of small molecules through lipid bilayers based on the free-energy reaction network (FERN) analysis. In this method, the collective variables (CVs) of the free energy calculations explicitly include the conformational changes in the rotational bonds of the solute molecules. The advantages of the present method over the other method are that it is possible to estimate reaction pathways and their reaction rates, i.e., permeation coefficients or passage times, in multidimensional space spanned by CVs though conventional methods such as the umbrella sampling method and target MDs often dealt with a few degrees of freedom. To demonstrate the efficacy of our method, we calculate the coefficients of the permeation of three small aromatic peptides, namely N-acetylphenylalanineamide (Ac-Phe-NH2 or NAFA), N-acetyltyrosineamide (Ac-Tyr-NH2 or NAYA), and N-acetyltryptophanamide (Ac-Trp-NH2 or NATA), through a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayer. In these cases we adopted one CV for the permeation direction and four CVs for the internal rotational coordinates. The results reveal that the permeation coefficients of NAFA, NAYA, and NATA are 1.7 × 10-2, 0.51 × 10-4, and 5.7 × 10-4 cm s-1, respectively. Compared with the experimental data, our simulation results followed the same trend, i.e., NAFA > NATA > NAYA. By analyzing the structures of metastable points of the solute molecules, our simulation result reveals that the aforementioned trend is caused by the differences in stability among their rotamers. Furthermore, we evaluate the statistical fluctuation of the rotamers, and the time scale of flipping the side chain reveals that the structures rigidify as the ligand moves deeper into the membrane.

Transcatheter aortic valve implantation under lower activated clotting time in a patient with hemorrhagic gastric cancer: a case report.

BACKGROUND: Perioperative management of transcatheter aortic valve implantation (TAVI) in patients with a high risk of bleeding requires careful consideration. CASE PRESENTATION: A 74-year-old man complained of chest pain and was admitted to our hospital. Close examination revealed severe aortic stenosis (AS) and hemorrhagic gastric cancer. Hemorrhage from gastric cancer was controlled using endoscopic hemostasis. While both gastric cancer and AS required surgery, we decided to perform transfemoral transcatheter aortic valve implantation (TAVI) under monitored anesthesia. To reduce bleeding from gastric cancer, we carefully adjusted the heparin dose to maintain the activated clotting time (ACT) between 180 and 200 s. TAVI with a balloon-expandable valve was completed without thrombotic complications. Laparoscopic distal gastrectomy was performed on the 6th day after TAVI. CONCLUSIONS: We report the successful management of TAVI in a patient with hemorrhagic gastric cancer. In TAVI for patients with hemorrhagic diseases, careful consideration of antithrombotic therapy is required.

Analytical Method Using a Scaled Hypersphere Search for High-Dimensional Metadynamics Simulations.

Metadynamics (MTD) is one of the most effective methods for calculating the free energy surface and finding rare events. Nevertheless, numerous studies using MTD have been carried out using 3D or lower dimensional collective variables (CVs), as higher dimensional CVs require costly computational resources and the obtained results are too complex to understand the important events. The latter issue can be conveniently solved by utilizing the free energy reaction network (FERN), which is a graph structure consisting of edges of minimum free energy paths (MFEPs), nodes of equation (EQ) points, and transition state (TS) points. In the present article, a new method for exploring FERNs on high-dimensional CVs using MTD and the scaled hypersphere search (SHS) method is described. A test calculation based on the MTD-SHS simulation of met-enkephalin in explicit water with 7 CVs was conducted. As a result, 889 EQ points and 1805 TS points were found. The MTD-SHS approach can find MFEPs exhaustively; therefore, the FERNs can be estimated without any a priori knowledge of the EQ and TS points.

Linear Response Functions of Densities and Spin Densities for Systematic Modeling of the QM/MM Approach for Mono- and Poly-Nuclear Transition Metal Systems.

We applied our analysis, based on a linear response function of density and spin density, to two typical transition metal complex systems-the reaction centers of P450, and oxygen evolving center in Photosystem II, both of which contain open-shell transition metal ions. We discuss the relationship between LRF of electron density and spin density and the types of units and interactions of the systems. The computational results are discussed in relation to quantum mechanics (QM) cluster and quantum mechanics/molecular mechanics (QM/MM) modeling that are employed to compute the reaction centers of enzymes.

Automated Search of Minimum Free-Energy Path by Umbrella Integration.

The free-energy landscape is an important factor for understanding the conformational equilibria of chemical reactions, and many techniques have been developed to calculate the potential of the mean force. Unfortunately, these methods require a previous knowledge of the system for calculations because the results depend on the reaction coordinates. In this study, we combine the scaled hypersphere search method with the umbrella integration method to obtain the transition states on free-energy landscapes and minimum-free-energy paths (MFEPs). With this approach, the MFEP connections between known and unknown equilibrium points are constructed without the prior knowledge of the free-energy landscape. The problem of reaction coordinates can be solved by using a multidimensional, fully automated interrogation of MFEPs for acquiring the potential of mean force. The efficiency of the proposed method is demonstrated by applying it to alanine dipeptide and alanine tripeptide. © 2018 Wiley Periodicals, Inc.

Automated Exploration of Free Energy Landscapes Based on Umbrella Integration.

We present a new approach for automated exploration of free energy landscapes on the basis of the umbrella integration (UI) method. The method to search points in the landscape relies on the normal distributions and gradients of the potential of mean force (PMF) obtained from UI calculations. We applied this approach to the alanine dipeptide in solution and demonstrated that the equilibrium and the transition states were efficiently found in the ascending order of the PMF values.

Linear Response Function of Bond-Order.

We present the linear response function of bond-orders (LRF-BO) based on a real space integration scheme for molecular systems. As in the case of the LRF of density, the LRF-BO is defined as the response of the bond order of the molecule for the virtual perturbation. Our calculations show that the LRF-BO enables us not only to detect inductive and resonating effects of conjugating systems, but also to predict pKa values on substitution groups via linear relationships between the Hammett constants and the LRF-BO values for meta- and para-substituted benzoic acids. More importantly, the LRF-BO values for the O-H bonds strongly depend on the sites to which the virtual perturbation is applied, implying that the LRF-BO values include essential information about reaction mechanism of the acid-dissociation of substituted benzoic acids.

Theoretical investigation on nearsightedness of finite model and molecular systems based on linear response function analysis.

We examined nearsightedness of electronic matter (NEM) of finite systems on the basis of linear response function (LRF). From the computational results of a square-well model system, the behavior of responses obviously depends on the number of electrons (N): as N increases, LRF, δρ(r)/δv(r'), decays rapidly for the distance, |r-r'|. This exemplifies that the principle suggested by Kohn and Prodan holds even for finite systems: the cause of NEM is destructive interference among electron density amplitudes. In addition, we examined double-well model systems, which have low-lying degenerate levels. In this case, there are two types of LRF: the cases of the half-filled and of full-filled in low-lying degenerate levels. The response for the former is delocalized, while that of the later is localized. These behaviors of model systems are discussed in relation to the molecular systems' counterparts, H2, He22+, and He2 systems. We also see that NEM holds for the dissociated limit of H2, of which the mechanism is similar to that of the insulating state of solids as suggested by Kohn. We also examined LRF of alanine tripeptide system as well as butane and butadiene molecules, showing that NEM of the polypeptide system is caused by sp3 junctions at Cα atoms that prevent propagation of amplitudes of LRF, which is critically different from that of NEM for finite and infinite homogeneous systems.