Multipole electrostatic potential derived atomic charges in NDDO-methods with <Emphasis Type="Italic">spd</Emphasis>-basis sets

The recently introduced multipole approach for computing the molecular electrostatic potential (MEP) within the semiempirical neglect of diatomic differential overlap (NDDO) framework [Horn AHC, Lin Jr-H., Clark T (2005) Theor Chem Acc 114:159–168] has been used to obtain atomic charges of nearly ab initio quality by scaling the semiempirical MEP. The parameterization set comprised a total of 797 compounds and included not only the newly parameterized AM1* elements Al, Si, P, S, Cl, Ti, Zr, and Mo but also the standard AM1 elements H, C, N, O and F. For comparison, the ZDO-approximated MEP was also calculated analytically in the spd-basis. For the AM1*-optimized structures, single-point calculations at the B3LYP, HF and MP2 levels with the 6-31G(d) and LanL2DZP basis sets were performed to obtain the MEP. The regression analysis of all 12 combinations of semiempirical and ab initio MEP data yielded correlation coefficients of at least 0.99 in all cases. Scaling the analytical and multipole-derived semiempirical MEP by the regression coefficients yielded mean unsigned errors below 2.6 and 1.9 kcal mol⁻¹, respectively. Subsequently, for 22 drug molecules from the World Drug Index, atomic charges were computed according to the RESP procedure using XX/6-31G(d) (XX=B3LYP, HF, MP2) and scaled AM1* multipole MEP; the correlation coefficients obtained are 0.83, 0.85 and 0.83, respectively. Figure: Schematic representation of the atomic charge generation: The molecular electrostatic potential (MEP) is calculated using the AM1* Hamiltonian; then the semiempirical MEP is scaled to DFT or ab initio level, and atomic charges are generated subsequently by the restraint electrostatic potential (RESP) fit method. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorized users. Proceedings of “Modeling Interactions in Biomolecules II”, Prague, September 5th–9th, 2005.     

功能性新型冠状病毒RBD结构域在毕赤酵母表面的展示*

目的:设计并构建新型冠状病毒(SARS-CoV-2)受体结合结构域(receptor binding domain,RBD)在毕赤酵母表面的展示体系,并对表面展示的RBD进行功能性评价,从而为以RBD为靶点的高通量药物筛选平台奠定基础。方法:将四种锚定分子与新冠病毒RBD融合,电转化至毕赤酵母中;通过细胞免疫荧光分析,筛选能够成功展示RBD的锚定系统;进一步分析其与血管紧张素转化酶2(angiotensin-converting enzyme 2,ACE2)受体的亲和力,证明展示在细胞表面RBD分子的功能。结果:仅Sed1p锚定分子能够有效呈递RBD至毕赤酵母细胞表面,展示效率约为70%;亲和力分析结果表明,ACE2受体和表面展示RBD的亲和力(K_D = 30.42 nmol/L)与溶液中RBD的亲和力(K_D = 16.00 nmol/L)较为接近。结论:这一体系能够在毕赤酵母表面高效地展示具有生物学功能的RBD,可用于抗新冠病毒RBD药物的高通量筛选和评价。     

Distribution of innervation zone and muscle fiber conduction velocity in the biceps brachii muscle

The spatial distributions of muscle innervation zone (IZ) and muscle fiber conduction velocity (CV) were examined in nine healthy young male participants. High-density surface electromyography (EMG) was collected from the biceps brachii muscle when subjects performed isometric elbow flexions at 20% to 80% of the maximal voluntary contraction (MVC). A total of 9498 samples of IZs were identified and CVs were calculated using the Radon transform. The center and width of IZ sample distribution were compared within four different force levels and six medial to lateral electrode column positions using repeated measures ANOVA and multiple comparison tests. Significant shifts of IZ center were observed in the medial columns (Columns 5, 6, and 7) compared with the lateral columns (Columns 3 and 4) (p < 0.05). Similarly, significant differences in the IZ width were found in Column 7 and 8 compared to Column 3 (p < 0.05). In contrast, muscle CV was unaffected by column position. Instead, muscle CV was faster at 40% and 80% MVC compared to 20% MVC (p < 0.05). The findings of this study add further insights into the physiological properties of the biceps brachii muscle.     

Effects of a tongue training program in Parkinson's disease: Analysis of electrical activity and strength of suprahyoid muscles

ObjectiveTo assess the electrical activity of the suprahyoid muscle and the tongue pressure in a two-wing program of tongue strengthening in individuals with Parkinson's disease (PD).MethodsA pre-post-detraining design study included sixty PD patients assigned to two groups randomly. The experimental group (EG) performed tongue isometric pressure exercises using the Iowa Oral Performance Instrument with an increasing scheme of 5% load weekly and traditional tongue therapy for 8 weeks. The control group (CG) performed only traditional therapy. The electrical activity of suprahyoids was measured using surface electromyography (sEMG) during tongue-to-palate pressure. Four selected domains of the Swallowing Quality of Life Questionnaire (SWAL-QOL) mostly related to tongue strength were considered.ResultsThe experimental group showed increased sEMG values of suprahyoid muscles reaching statistically significant difference at the fourth week of tongue training, while the control did it at the eighth week. Experimental group showed significant improvements in tongue strength (d = 2.128; p = 0.000). Only controls showed detraining effect. Statistically significant difference within groups were found in one and three dimensions of the SWAL-QOL in the CG and EG, respectively.ConclusionAnalysis of electrical activity on suprahyoids muscles provided a better understanding of the changes underlying the outcomes of tongue strength gains obtained through a combined tongue strengthening exercises protocol in PD. Such protocol led not only to increased tongue strength but also to a better perceived swallowing function in PD subjects.     

Regional variations of in vivo surface stiffness of soft tissue layers of musculoskeletal extremities

Surface stiffness of bulk soft tissue in musculoskeletal extremities is important to consider in the design of prosthetics, exoskeletons, and protective gear. This knowledge is also foundational for surgical simulation and clinical interventions leveraging manipulation of the musculoskeletal surfaces. Injuries to musculoskeletal extremities are common and surgical and preventive interventions require interactions between various objects such as surgical tools and support surfaces with tissue boundaries. While a handful of investigations examined the variations in indentation mechanics due to pathology or injury specific sites, a comprehensive analysis across the surfaces of musculoskeletal extremities has not been completed. In this study we examine variations of surface stiffness across 8 sites of the upper and lower arms and legs for 95 subjects using an instrumented ultrasound device. Differences in surface stiffness were observed between gender, activity level, and indentation location groups. The lower arm posterior location had the highest average stiffness (3.89 × 10⁻³ MPa/mm), while the lowest stiffness was observed at the upper leg posterior location (0.98 × 10⁻³ MPa/mm). The differences between indentation sites were larger in magnitude when compared to differences due to demographics (gender and activity level). However the large ranges of the 95% confidence intervals suggest that an aggregated metric based on population or sub-group may not capture individual variations. This study implicates the motivation to explore tissue composition variations within the indentation sites as well as the potential importance to include variations in surface stiffness during surgical simulations.     

Effect of synthetic surfactants and soapwort (Saponaria officinalis L.) extract on skin-mimetic model lipid monolayers

The effect of a saponin-rich extract from rhizomes of Soapwort (Saponaria officinalis L) and four synthetic surfactants: sodium lauryl sulphate (SLS), sodium laureth sulphate (SLES), ammonium lauryl sulphate (ALS) and cocamidopropyl betaine (CAPB) on two model lipid monolayers is analyzed using surface pressure, surface dilatational rheology and fluorescence microscopy. The following monolayers were employed: dipalmitoylphosphatidylcholine/cholesterol mixture in a molar ratio of 7:3 (DPPC/CHOL) and Ceramide [AP]/stearic acid/cholesterol in a molar ratio of 14:14:10 (CER/SA/CHOL). They mimicked a general bilayer structure and an intercellular lipid mixture, respectively. Both lipid mixtures on Milli-Q water were first compressed to the initial surface pressure, Π₀ = 30 mN/m and then the subphase was exchanged with the respective (bio)surfactant solution at 1% (w/w). All four synthetic surfactants behaved in a similar way: they increased surface pressure to about 40 mN/m and reduced the storage modulus of surface dilational surface rheology, E′, to the values close to zero. The corresponding fluorescence microscopy pictures confirmed that the lipids mimicking the stratum corneum components were almost completely removed by the synthetic surfactants under the present experimental conditions. The components of the Soapwort extract (SAP) increased surface pressure to significantly higher values than the synthetic surfactants, but even more spectacular increase was observed for the storage modulus of the SAP-penetrated lipid monolayers (up to E′= 715 mN/m).     

Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI

Factor XI (FXI), the zymogen of activated FXI (FXIa), is an attractive target for novel anticoagulants because FXI inhibition offers the potential to reduce thrombosis risk while minimizing the risk of bleeding. BAY 1213790, a novel anti-FXIa antibody, was generated using phage display technology. Crystal structure analysis of the FXIa–BAY 1213790 complex demonstrated that the tyrosine-rich complementarity-determining region 3 loop of the heavy chain of BAY 1213790 penetrated deepest into the FXIa binding epitope, forming a network of favorable interactions including a direct hydrogen bond from Tyr102 to the Gln451 sidechain (2.9 Å). The newly discovered binding epitope caused a structural rearrangement of the FXIa active site, revealing a novel allosteric mechanism of FXIa inhibition by BAY 1213790. BAY 1213790 specifically inhibited FXIa with a binding affinity of 2.4 nM, and in human plasma, prolonged activated partial thromboplastin time and inhibited thrombin generation in a concentration-dependent manner.     

Numerical simulations of surface plasmon resonance system for monitoring DNA hybridization and detecting protein-lipid film interactions

This paper presents a simple method to extract information about thin organic films from surface plasmon resonance (SPR) spectra. From numerical simulations it was found that a shift (Δθ _SPR) of an absorption peak in the SPR spectrum was directly proportional to the product of the thin organic film thickness and the refractive index difference between the thin organic film and a buffer soaking the sample. It was also found that Δθ _SPR was not sensitive to the thin organic film support of a gold film and a glass cover slip. Relationships between Δθ _SPR and distributions of macromolecule structures, in the thin organic films were theoretically established. Formulae were derived for a homemade SPR system to calculate length, transverse area, density and surface concentration of macromolecules in the thin organic film. The validity of these treatments was checked by precisely measuring the size of a single distearoylphosphatidylcholine molecule on a gold-supported phospholipid film; by quantitatively monitoring hybridization of synthesized oligonucleotides strands based on a biotin/avidin system; and by quantitatively detecting the steric hindrance of rabbit C-reactive protein specifically bound to phospholipid monolayers composed of synthesized lipids. Received: 4 May 1998 / Revised version: 27 July 1998 / Accepted: 27 August 1998     

Real-Time, label-free monitoring of tumor antigen and serum antibody interactions

Conventional techniques for the detection of biomolecular interactions can be limited by the need for exogenous labels, time- and labor-intensive protocols, as well as by poor sensitivity levels. A refractometer instrument has been reconfigured to detect biomolecular interactions through changes in surface plasmon resonance (SPR). The binding kinetics and affinity values of anti-NY-ESO-1 monoclonal antibody, ES121, to the cancer-testis antigen NY-ESO-1 were determined according to the surface heterogeneity model and resulted in K(D) values of 1.3x10(-9) and 2.1x10(-10) M. The reconfigured instrument was then used to measure the interaction between tumor antigens and serum antibodies against these antigens in preselected cancer patient sera samples. The tumor antigens assayed included NY-ESO-1, SSX2 and p53, all used as recombinant proteins containing polyhistidine tags. These results demonstrated that the instrument is capable of detecting the binding of serum antibodies from cancer patient sera to immobilized tumor antigens, consistent with those observed previously in ELISA-based experiments. These results demonstrate the potential of SPR technology for the rapid diagnosis and monitoring immune responses.