Molecular docking using surface complementarity

A method is described to dock a ligand into a binding site in a protein on the basis of the complementarity of the inter-molecular atomic contacts. Docking is performed by maximization of a complementarity function that is dependent on atomic contact surface area and the chemical properties of the contacting atoms. The generality and simplicity of the complementarity function ensure that a wide range of chemical structures can be handled. The ligand and the protein are treated as rigid bodies, but displacement of a small number of residues lining the ligand binding site can be taken into account. The method can assist in the design of improved ligands by indicating what changes in complementarity may occur as a result of the substitution of an atom in the ligand. The capabilities of the method are demonstrated by application to 14 protein–ligand complexes of known crystal structure. © 1996 Wiley Liss, Inc.     

A dual function activity-dependent,muscle-specific enhancer from rat nicotinic acetylcholine receptor δ-subunit gene

Nicotinic acetylcholine receptors (nAChR) mediate communication between nerve and muscle. The expression of these receptors increases dramatically during muscle development when myoblasts are fusing into multinucleated myotubes. The molecular mechanisms mediating this muscle developmental stage specific expression are not well understood. We report here the identification of nAChR δ-subunit promoter DNA sequences that differentially interact with nuclear proteins isolated from myoblasts, myotubes, and nonmuscle cells. The functional role these sequences play in mediating muscle-specific expression was explored using mutagenesis and enhancer assays. These studies resulted in the identification of a 47-bp muscle-specific enhancer that mediates increased expression of the nAChR δ-submit gene during myotube formation. This enhancer contains an E-box and an element with similarity to the SV40 core enhancer (SVCE). Point mutations throughout this 47-bp enhancer showed that the E-box and the SVCE sequence are both necessary for conferring muscle-specific expression onto a heterologous promoter. Interestingly, this same DNA sequence also functions as an activity-dependent enhancer. © 1996 John Wiley & Sons, Inc.     

The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Heparin, a naturally occurring glycosaminoglycan, has been found to have antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19. To elucidate the mechanistic basis for the antiviral activity of heparin, we investigated the binding of heparin to the SARS-CoV-2 spike glycoprotein by means of sliding window docking, molecular dynamics simulations, and biochemical assays. Our simulations show that heparin binds at long, positively charged patches on the spike glycoprotein, thereby masking basic residues of both the receptor-binding domain (RBD) and the multifunctional S1/S2 site. Biochemical experiments corroborated the simulation results, showing that heparin inhibits the furin-mediated cleavage of spike by binding to the S1/S2 site. Our simulations showed that heparin can act on the hinge region responsible for motion of the RBD between the inactive closed and active open conformations of the spike glycoprotein. In simulations of the closed spike homotrimer, heparin binds the RBD and the N-terminal domain of two adjacent spike subunits and hinders opening. In simulations of open spike conformations, heparin induces stabilization of the hinge region and a change in RBD motion. Our results indicate that heparin can inhibit SARS-CoV-2 infection by three mechanisms: by allosterically hindering binding to the host cell receptor, by directly competing with binding to host heparan sulfate proteoglycan coreceptors, and by preventing spike cleavage by furin. Furthermore, these simulations provide insights into how host heparan sulfate proteoglycans can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.     

Biogeographic consequences of shifting climate for the western massasauga (Sistrurus tergeminus)

The western massasauga (Sistrurus tergeminus) is a small pit viper with an extensive geographic range, yet observations of this species are relatively rare. They persist in patchy and isolated populations, threatened by habitat destruction and fragmentation, mortality from vehicle collisions, and deliberate extermination. Changing climates may pose an additional stressor on the survival of isolated populations. Here, we evaluate historic, modern, and future geographic projections of suitable climate for S. tergeminus to outline shifts in their potential geographic distribution and inform current and future management. We used maximum entropy modeling to build multiple models of the potential geographic distribution of S. tergeminus. We evaluated the influence of five key decisions made during the modeling process on the resulting geographic projections of the potential distribution, allowing us to identify areas of model robustness and uncertainty. We evaluated models with the area under the receiver operating curve and true skill statistic. We retained 16 models to project both in the past and future multiple general circulation models. At the last glacial maximum, the potential geographic distribution associated with S. tergeminus occurrences had a stronghold in the southern part of its current range and extended further south into Mexico, but by the mid‐Holocene, its modeled potential distribution was similar to its present‐day potential distribution. Under future model projections, the potential distribution of S. tergeminus moves north, with the strongest northward trends predicted under a climate scenario increase of 8.5 W/m². Some southern populations of S. tergeminus have likely already been extirpated and will continue to be threatened by shifting availability of suitable climate, as they are already under threat from desertification of grasslands. Land use and habitat loss at the northern edge of the species range are likely to make it challenging for this species to track suitable climates northward over time.     

The Distribution of Perkinsus marinus in Gulf Coast Oysters: Its Relationship with Temperature,Reproduction, and Pollutant Body Burden

Oysters from 48 Gulf of Mexico sites were examined for presence and infection intensity of the endoparasite, Perkinsus (= Dermocystidium) marinus (Mackin, Owen and Collier, 1950) as part of NOAA's Status and Trends Mussel Watch Program. Prevalence exceeded 75% at 25 sites. Infection intensity did not vary with sex or reproductive stage. Latitude, total polynuclear aromatic hydrocarbon (PAH) content and industrial and agricultural land use significantly affected the parasite's distribution. PAH and pesticide concentrations were latitudinally dependent, suggesting an impact of spawning frequency on uptake and depuration. P. marinus analysis complements the use of pollutant body burden for determining change in environmental quality because it responds differently than pollutant body burden to the biology and ecology of the oyster.     

Theoretical study of flow,pressure and solute concentration in double membrane systems

A model system consisting of two rigidly held membranes in series was investigated through the application of the Kedem and Katchalsky thermodynamic single membrane flow equations. This analysis results in predictions of the steady state flow properties as well as values for the solute concentration and pressure of the internal compartment when the system is under the influence of a constant solute concentration or hydrostatic pressure gradient. It is demonstrated that although the flow properties and internal compartment pressure are complicated functions of the membrane permeability coefficients and driving gradient across the system, the relationships are greatly simplified by the explicit appearance of the internal compartment steady state solute concentration in the equations. It is shown that the steady state volume flow rate depends on the absolute value of the solute concentration in the external compartments, as well as the solute concentration gradient across the system. The properties of non-linear dependence of volume flow on concentration gradient, and rectification of volume flow are discussed and shown to be independent properties of the system. For the system under the influence of a solute concentration gradient, the internal compartment pressure can be greater or less than the ambient pressure, and depends mainly on the order in which the membranes are encountered by the volume flow. These properties are qualitatively correlated with certain available experimental observations in biological systems.     

Conformation of the Drosophila motor protein non-claret disjunctional in solution from X-ray and neutron scattering

The quaternary structures of monomeric and dimeric Drosophila non-claret disjunctional (ncd) constructs were investigated using synchrotron x-ray and neutron solution scattering, and their low resolution shapes were restored ab initio from the scattering data. The experimental curves were further compared with those computed from crystallographic models of one monomeric and three available dimeric ncd structures in the microtubule-independent ADP-bound state. These comparisons indicate that accounting for the missing parts in the crystal structures for all these constructs is indispensable to obtain reasonable fits to the scattering patterns. A ncd construct (MC6) lacking the coiled-coil region is monomeric in solution, but the calculated scattering from the crystallographic monomer yields a poor fit to the data. A tentative configuration of the missing C-terminal residues in the form of an antiparallel beta-sheet was found that significantly improves the fit. The atomic model of a short dimeric ncd construct (MC5) without 2-fold symmetry is found to fit the data better than the symmetric models. Addition of the C-terminal residues to both head domains gives an excellent fit to the x-ray and neutron experimental data, although the orientation of the beta-sheet differs from that of the monomer. The solution structure of the long ncd construct (MC1) including complete N-terminal coiled-coil and motor domains is modeled by adding a straight coiled-coil section to the model of MC5.     

On indirect genetic effects in structured populations

Indirect genetic effects (IGEs) occur when the phenotype of an individual, and possibly its fitness, depends, at least in part, on the genes of its social partners. The effective result is that environmental sources of phenotypic variance can themselves evolve. Simple models have shown that IGEs can alter the rate and direction of evolution for traits involved in interactions. Here we expand the applicability of the theory of IGEs to evolution in metapopulations by including nonlinear interactions between individuals and population genetic structure. Although population subdivision alone generates some dramatic and nonintuitive evolutionary dynamics for interacting phenotypes, the combination of nonlinear interactions with subdivision reveals an even greater importance of IGEs. The presence of genetic structure links the evolution of interacting phenotypes and the traits that influence their expression ("effector traits") even in the absence of genetic correlations. When nonlinear social effects occur in subdivided populations, evolutionary response is altered and can even oppose the direction expected due to direct selection. Because population genetic structure allows for multilevel selection, we also investigate the role of IGEs in determining the response to individual and group selection. We find that nonlinear social effects can cause interference between levels of selection even when they act in the same direction. In some cases, interference can be so extreme that the actual evolutionary response to multilevel selection is opposite in direction to that predicted by summing selection at each level. This theoretical result confirms empirical data that show higher levels of selection cannot be ignored even when selection acts in the same direction at all levels.