Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character最新文献

{"title":"Automated site-directed drug design: the formation of molecular templates in primary structure generation.","authors":"R A Lewis,&nbsp;P M Dean","doi":"10.1098/rspb.1989.0018","DOIUrl":"https://doi.org/10.1098/rspb.1989.0018","url":null,"abstract":"<p><p>In this paper the spacer skeleton concept is used to produce molecular graphs of putative ligands for binding sites. The skeletons are transformed into molecular templates within the constraints of the accessible surface of the ligand-binding site. A distance-matrix method is used to compare ligand points with vertices of the spacer skeleton through a permutation of all possible correspondences. A tolerance parameter is used to screen for poor matches. As a result, a small number of matched vertices and ligand points are produced. These are fitted into the site by a constrained optimization routine using an analytical function. Ligand points fall within the site and are optimally positioned adjacent to the corresponding site points; other vertices of the spacer skeleton lying beneath the accessible surface of the site are clipped off. A molecular template is thereby formed with its vertices linked to the ligand points. The final step is to verify that the bonding integrity of the skeleton remains. The computational methods outlined in this paper have been tested at two binding sites: the pteridine binding site in dihydrofolate reductase and the amidinophenylpyruvate site of trypsin. Molecular graphs for both sites were generated automatically; they showed strong similarity to those of the natural ligands.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1283","pages":"141-62"},"PeriodicalIF":0.0,"publicationDate":"1989-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13709229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated site-directed drug design: the concept of spacer skeletons for primary structure generation.","authors":"R A Lewis,&nbsp;P M Dean","doi":"10.1098/rspb.1989.0017","DOIUrl":"https://doi.org/10.1098/rspb.1989.0017","url":null,"abstract":"<p><p>This paper examines the problem of automated structure generation at specified binding sites. The objective is to obtain molecular graphs that span the binding site and incorporate predicted ligand points at their vertices. Three approaches are considered: brute-force techniques, subgraph addition and spacer skeletons. Spacer skeletons are assemblies of molecular subgraphs and are used to reduce the combinatorial problems of structure generation to a practicable level for future analysis. This description is restricted to structure generation in two dimensions. Assemblies of rings are examined for planarity by searching the Cambridge Structural Database. Appropriate spacer skeletons may then be fitted to arrays of site points.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1283","pages":"125-40"},"PeriodicalIF":0.0,"publicationDate":"1989-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13709228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Properties of membrane ion conductances evoked by hormonal stimulation of guinea-pig and rabbit isolated hepatocytes.","authors":"T Capiod,&nbsp;D C Ogden","doi":"10.1098/rspb.1989.0020","DOIUrl":"https://doi.org/10.1098/rspb.1989.0020","url":null,"abstract":"<p><p>Membrane conductance changes evoked in isolated guinea-pig or rabbit hepatocytes by hormonal stimulation were studied with the whole-cell patch clamp technique. In Cl-containing solutions, noradrenaline (NA), ATP or angiotensin II (AII) evoked an increase of conductance to both K (GK) and Cl (GCl) ions. Activation of GK occurred after a delay of several seconds and was sustained in the presence of hormone. Activation of GCl was transient, lasting several seconds, and arose either at the same time or shortly after the increase in GK. Conductances showed an initial rapid rise and slow oscillatory changes during maintained hormone application. The NA-induced current reversed at -19 mV in Cl solutions, between the equilibrium potentials for chloride (ECl = 0 mV) and potassium ions (EK = -85 mV), and at -75 mV, near EK, in Cl-free solution. In both conditions whole-cell current-voltage curves were linear in the range -100 mV to +40 mV. The conductance increase produced by NA to Cl- ions was about 50 nS, that to K+ ions was 6 nS. The potassium conductance increase was abolished by the polypeptide toxin apamin (50 nM). An increase in membrane current noise was associated with NA-evoked outward K+ current and blocked by apamin. Spectral analysis gave estimates of the elementary K channel conductance of 1.7 pS. Power spectra were fitted by two Lorentzian components, with average half-power frequencies of 2 and 190 Hz. These results are discussed in relation to the single-channel properties and indicate that the open probability of K channels during the NA response is high. In Cl solutions, with apamin to block the K conductance, no increase in current noise was detected during the large Cl conductance evoked by NA. This suggests either that Cl channels are of very low unitary conductance (less than 1 pS) or that Cl transport is due to a membrane carrier. The complex time-course of hormonally evoked conductances is not due to the properties of ion conductances per se but probably to underlying changes of intracellular second-messenger concentration.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1283","pages":"187-201"},"PeriodicalIF":0.0,"publicationDate":"1989-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13709230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated site-directed drug design: the prediction and observation of ligand point positions at hydrogen-bonding regions on protein surfaces.","authors":"D J Danziger,&nbsp;P M Dean","doi":"10.1098/rspb.1989.0016","DOIUrl":"https://doi.org/10.1098/rspb.1989.0016","url":null,"abstract":"<p><p>The HSITE program proposed in the previous paper was written to define putative ligand-point regions that could be found at protein surfaces. These regions would represent positions for hydrogen-bonding acceptor and donor atoms. In this paper the prediction of the location of these regions is compared with: (1) the position of the oxygen atoms of water molecules on the hydrated proteins myoglobin and plastocyanin; and (2) the position of hydrogen-bonded atoms in methotrexate and NADPH co-crystallized with dihydrofolate reductase, and in amidinophenyl-pyruvate co-crystallized with trypsin. The prediction of ligand-point regions is in agreement with the surveys of experimental data for water-molecule positions in protein crystals and with the positions of hydrogen-bonding atoms found in co-crystallized ligands.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1283","pages":"115-24"},"PeriodicalIF":0.0,"publicationDate":"1989-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13709227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early social status and the development of life-history strategies in Atlantic salmon.","authors":"N B Metcalfe,&nbsp;F A Huntingford,&nbsp;W D Graham,&nbsp;J E Thorpe","doi":"10.1098/rspb.1989.0009","DOIUrl":"https://doi.org/10.1098/rspb.1989.0009","url":null,"abstract":"<p><p>Atlantic salmon have a variable life cycle. In good growing conditions, underyearling fish may metamorphose into the migratory smolt phase during their second spring, or delay at least a further year. The strategy adopted by particular fish appears to become fixed during their first summer. This paper examines whether either feeding efficiency or dominance in mid-summer correlates with the life-history strategy adopted. Eighty fish were individually marked and their feeding efficiency (= mean handling time for food items) and dominance rank measured under laboratory conditions in mid-July. Growth rates of the fish were then monitored over the next three months, until developmental strategies became apparent. Discriminant and logistic regression analyses revealed that both dominance rank and size attained by July were independent, significant predictors of future developmental pattern (the age at metamorphosis being correctly predicted on the basis of rank and size in 84% of cases) whereas feeding efficiency had no effect. Thus fish that were dominant or larger two months after first feeding or both had a greater probability of migrating after only one year in freshwater than those more subordinate or smaller or both.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1282","pages":"7-19"},"PeriodicalIF":0.0,"publicationDate":"1989-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13709225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The award of medals by the president, Sir George Porter, at the anniversary meeting, 30 November 1988.","authors":"","doi":"10.1098/rspb.1989.0008","DOIUrl":"https://doi.org/10.1098/rspb.1989.0008","url":null,"abstract":"The Copley Medal is awarded to Sir Michael Atiyah, F. R. S., in recognition of his fundamental contributions to a wide range of topics in geometry, topology, analysis and theoretical physics. For a quarter of a century, Sir Michael Atiyah has been the unrivalled leader of mathematical research in Britain. His work spans a range unequalled among his contemporaries, including algebraic topology, algebraic and differential geometry, analysis and theoretical physics. Many of his pioneering contributions have been the seeds for extensive later developments. His most celebrated work centres around the Atiyah-Singer Index Theorem, which shows how the topological behaviour of a manifold influences the behaviour of elliptic partial differential equations over it. This is one of the great insights of twentieth-century mathematics. In a series of papers, he and his collaborators have explored its many variants and ramifications, and have opened up new directions in many areas of mathematics, breaking through the old divisions between topology, differential equations and functional analysis. In recent years he has been a leader in developing links between geometry and particle physics, and many of the topics he has helped develop are in the forefront of research by mathematicians and physicists in this new and active area.","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1282","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"1989-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13708617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential response to a competitor by Atlantic salmon adopting alternative life-history strategies.","authors":"N B Metcalfe","doi":"10.1098/rspb.1989.0010","DOIUrl":"https://doi.org/10.1098/rspb.1989.0010","url":null,"abstract":"<p><p>The life cycle of the Atlantic salmon is extremely variable. In good growing conditions, juvenile salmon either metamorphose into the migratory phase by their second spring, or delay this for at least another year. The strategy appears to be decided in their first summer. This study compared competitive responses of fish adopting the two strategies. Laboratory experiments showed that the two types of fish had similar foraging efficiencies in isolation. However, although a simulated competitor had little effect on the feeding behaviour of fast-developing fish, it caused an 18-fold increase in the incidence of failed feeding attempts by fish delaying development. The probability of an attack failing was dependent on how close the competitor came.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1282","pages":"21-7"},"PeriodicalIF":0.0,"publicationDate":"1989-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13708618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-mitochondrial calcium ion regulation in rat ventricular myocytes.","authors":"C H Fry,&nbsp;D P Harding,&nbsp;D J Miller","doi":"10.1098/rspb.1989.0012","DOIUrl":"https://doi.org/10.1098/rspb.1989.0012","url":null,"abstract":"Ca2+ exchange has been measured in a suspension of rat ventricular myocytes treated with digitonin or saponin to render the sarcolemma permeable to small molecules and ions. Two fractions of exchange were identified, one that was attributed to the mitochondrial component of the cell and the other to a non-mitochondrial fraction. Mitochondrial Ca2+ uptake was blocked by sodium azide and depended on respiratory substrates whereas non-mitochondrial uptake occurred independently of these molecules but was dependent on ATP and creatine phosphate. Non-mitochondrial Ca2+ uptake could be induced at a Ca2+ concentration below 1 um and the initial rate increased with concentration up to 100 um Uptake could be reversed by sulmazole (a caffeine-like substance) and this reversal in turn inhibited by ryanodine. These properties suggest that the major locus for non-mitochondrial Ca2+ exchange is at the sarcoplasmic reticulum. Ca2+ exchange could be modulated by a number of agents, including carnosine, but was unaffected by others, including Na+, inositol trisphosphate and cyclic AMP. A kinetic model of the data is presented, which incorporates similar data of Ca2+ uptake into the mitochondrial fraction. The rates of Ca2+ exchange measured in these experiments suggest that these two components of the cell can reduce the sarcoplasmic Ca2+ concentration rapidly enough to account for the observed transient nature of the isometric twitch. Furthermore, it is suggested that both non-mitochondrial and mitochondrial fractions of the cell could significantly contribute to tension relaxation in rat cardiac muscle.","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1282","pages":"53-77"},"PeriodicalIF":0.0,"publicationDate":"1989-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13709224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of post-perturbation gating kinetics of single ion channels.","authors":"F G Ball,&nbsp;R McGee,&nbsp;M S Sansom","doi":"10.1098/rspb.1989.0011","DOIUrl":"https://doi.org/10.1098/rspb.1989.0011","url":null,"abstract":"<p><p>Analysis of mean dwell-times as a function of the number of channel openings elapsed since a stepwise perturbation in ion-channel kinetics is shown to provide information concerning the topology of the underlying gating mechanism. The difference between the post-perturbation mean dwell-time and the corresponding equilibrium mean is shown to decay as the sum of Ng-1 geometric terms in k, the number of openings since the perturbation, where Ng is the minimum number of gateway states in the channel gating mechanism. The method is illustrated by consideration of various simple gating schemes. A modification of the method accommodating the presence of channel inactivation or desensitization is described. Application of the method to a delayed-rectifier type K+ channel of NG108-15 cells reveals that Ng greater than or equal to 2, consistent with a branched gating mechanism.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"236 1282","pages":"29-52"},"PeriodicalIF":0.0,"publicationDate":"1989-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13616001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amplifiers and the handicap principle in sexual selection: a different emphasis.","authors":"O Hasson","doi":"10.1098/rspb.1989.0006","DOIUrl":"https://doi.org/10.1098/rspb.1989.0006","url":null,"abstract":"<p><p>Population genetic models have shown that female choice is a potential cause of the evolution of male display. In these models the display is assumed to be the immediate object of female choice. Here I present an explicit genetic model that shows that male display can evolve as a consequence of female choice even when the display is not the immediate object of choice. When females initially base their preferences on the existence of variance in a cue that is correlated with male viability, a rare display can evolve to fixation if it amplifies the previously recognized differences in males, (i.e. if it increases the resolution power of females with respect to the original cue). By definition, amplifying displays (or amplifiers) increase mating success of the more viable males and decrease mating success of the less viable males. Therefore, the higher the frequency of the preferred, more viable males, the more likely it is that amplifiers will evolve to fixation. The evolution of an amplifier is further facilitated by a genetic association that is built up between the amplifier allele and the more viable allele. If the expression of the amplifier is limited to the more viable males, the amplifier will evolve to fixation provided only that the change in total fitness to the more viable males (higher mating success, lower viability), is positive.</p>","PeriodicalId":54561,"journal":{"name":"Proceedings of the Royal Society of London Series B-Containing Papers of Abiological Character","volume":"235 1281","pages":"383-406"},"PeriodicalIF":0.0,"publicationDate":"1989-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1098/rspb.1989.0006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13708449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}