PubMed Health⌕ Search

Biomedical subjects

S L Lin

Publications and source records attributed to S L Lin.

At least 19 recordsLinked to original sources
PubMed1995

Molecular surface complementarity at protein-protein interfaces: the critical role played by surface normals at well placed, sparse, points in docking.

Rigid-body docking of two molecules involves matching of their surfaces. A successful docking methodology considers two key issues: molecular surface representation, and matching. While approaches to the problem differ, they all employ certain surface geometric features. While surface normals are routinely created with molecular surfaces, their employment has surprisingly been almost completely overlooked. Here we show how the normals to the surface, at specific, well placed points, can play a critical role in molecular docking. If the points for which the normals are calculated represent faithfully and accurately the molecular surfaces, the normals can substantially ameliorate the efficiency of the docking in a number of ways. The normals can drastically reduce the combinatorial complexity of the receptor-ligand docking. Furthermore, they can serve as a powerful filter in screening for quality docked conformations. Below we show how deploying such a straight forward device, which is easy to calculate, large protein-protein molecules are docked with unparalleled short times and with a manageable number of potential solutions. Considering the facts that here we dock (1) two large protein molecules, including several large immunoglobulin-lysozyme complexes; (2) that we use the entire molecular surfaces, without a predefinition of the active sites, or of the epitopes, of neither the ligand nor the receptor; that (3) the docking is completely automated, without any labelling, or pre-specification, of the input structural database, and (4) with a single set of parameters, without any further tuning whatsoever, such results are highly desirable. This approach is specifically geared towards matching of the surfaces of large protein molecules and is not applicable to small molecule drugs.

Computer Graphics↗
PubMed1995

A geometry-based suite of molecular docking processes.

We have developed a geometry-based suite of processes for molecular docking. The suite consists of a molecular surface representation, a docking algorithm, and a surface inter-penetration and contact filter. The surface representation is composed of a sparse set of critical points (with their associated normals) positioned at the face centers of the molecular surface, providing a concise yet representative set. The docking algorithm is based on the Geometric Hashing technique, which indexes the critical points with their normals in a transformation invariant fashion preserving the multi-element geometric constraints. The inter-penetration and surface contact filter features a three-layer scoring system, through which docked models with high contact area and low clashes are funneled. This suite of processes enables a pipelined operation of molecular docking with high efficacy. Accurate and fast docking has been achieved with a rich collection of complexes and unbound molecules, including protein-protein and protein-small molecule associations. An energy evaluation routine assesses the intermolecular interactions of the funneled models obtained from the docking of the bound molecules by pairwise van der Waals and Coulombic potentials. Applications of this routine demonstrate the goodness of the high scoring, geometrically docked conformations of the bound crystal complexes.

Algorithms↗
PubMed1995

A study of four-helix bundles: investigating protein folding via similar architectural motifs in protein cores and in subunit interfaces.

Four-helix bundles are identified and characterized in the subunit interfaces of protein multimers. We find that this motif occurs as often in the interfaces as in the protein monomers. Common and different characteristics demonstrated by the bundles in the two environments suggest the possible stabilization mechanisms of the bundles via cooperative helical twist, dipole alignment and interhelical connections. Nucleation of parallel helix pairs may be a favourable pathway before the pairs couple into bundles during folding. Certain properties found chaotic in the interface four-helix bundles indicate that either the subunit association is far from the global minimum conformation, or that the footprints of the folding pathway are recorded in these properties.

Enzymes↗
PubMed1995

Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone. A randomized, digoxin-controlled study.

A 24 h intravenous dosing regimen of amiodarone was designed to reach a peak plasma concentration at 1 h and to maintain the concentration above a certain level during the infusion period. A randomized, open-label, digoxin-controlled study was undertaken to observe the efficacy and safety of the dosing regimen of amiodarone in treating recent-onset, persistent, atrial fibrillation and flutter with ventricular rates above 130 beats.min-1. Fifty patients with a mean age of 70 +/- 7 (SD) years were enrolled and randomly assigned to receive either amiodarone intravenously (n = 26) or digoxin (n = 24). Amiodarone HCl was infused over 24 h according to the following regimen: 5 mg.min-1, 3 mg.min-1, 1 mg.min-1 and 0.5 mg.min-1 for 1, 3, 6 and 14 h, respectively, for a 70-kg subject. Digoxin (0.013 mg.kg-1) was infused in three divided doses, each dose 2 h apart and infused over 30 min. The mean heart rates in the amiodarone group decreased significantly from 157 +/- 20 beats.min-1 to 122 +/- 25 beats.min-1 after 1 h (P < 0.05 vs baseline), and then decreased further to stabilize at 96 +/- 25 beats.min-1 after 6 h (P < 0.05). The digoxin group had fewer dramatic alterations in heart rates, compared to the amiodarone group, in the first 8 h (P < 0.05, respectively). Maximum reduction was reached only after 8 h. The amiodarone infusion was prematurely aborted in two patients due to severe bradycardia and death after conversion in one patient and aggravation of heart failure in the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Functional domains of delta antigens and viral RNA required for RNA packaging of hepatitis delta virus.

The functions of delta antigens (HDAgs) in the morphogenesis of hepatitis delta virus (HDV) have been studied previously. The C terminus of large HDAg has been shown to complex with the small surface antigen (HBsAg) of helper hepatitis B virus, whereas the assembly of small HDAg requires interaction with the N terminus of large HDAg (M.-F. Chang, C.-J. Chen, and S. C. Chang, J. Virol. 68:646-653, 1994). To further examine the molecular mechanisms by which HDAgs are involved in the assembly of HDV RNA, we have cotransfected Huh-7 cells with plasmids representing a longer than unit-length HDV and the small HBsAg cDNAs. We found that HDAg mRNA could be generated from an endogenous promoter within the HDV cDNA that was translated into large HDAg. Large HDAg is capable of complexing with monomeric HDV genomic RNA to form ribonucleoprotein particles (RNPs) and is capable of forming enveloped HDV-like particles in the presence of small HBsAg without undergoing HDV replication. In addition, the middle region from amino acid residues 89 to 145 of large HDAg is required for assembly of the RNPs but is dispensable for assembly of the enveloped particles. RNA assembly is also demonstrated with small HDAg when it is cotransfected with a packaging-defective large HDAg mutant and small HBsAg. Leu-115 within the putative helix-loop-helix structure of the small HDAg is important for the replication of HDV but is not essential for RNA assembly, suggesting that conformational requirements of small HDAg for replication and assembly of viral RNA may be different. Further studies indicate that a 312-nucleotide linear HDV RNA from one end of the HDV and structure is sufficient to form RNP complexes competent for assembly of virus-like particles with large HDAg and small HBsAg.

Antigens, Viral↗
PubMed1995

Carcinosarcoma of the salivary gland on CT.

Three cases of carcinosarcoma of the salivary gland, two in the submandibular gland, and one in the parotid, were investigated with CT and exhibited a variety of findings. The density of the tumors was lower than that of normal submandibular tissue. A calcification was found in one case. One case showed extensive lymphadenopathy. The parotid lesion had low central density with an enhancing margin.

Aged↗
PubMed1995

Zygomycotic lung abscess: a case report.

Zygomycosis is an uncommon, but frequently fatal, fungal infection caused by members of the class Zygomycetes. The risk factors include diabetes mellitus, uremia, leukemia and use of deferoxamine as an iron-chelating agent; healthy persons also are occasionally infected. Those fungi, spread by their ubiquitous spores, most frequently involve the respiratory system. Rhinocerebral zygomycosis occurs predominantly in patients with uncontrolled diabetic ketoacidosis. Pulmonary zygomycosis most frequently is observed in granulocytopenic and corticosteroid-treated patients. Other clinical manifestations are gastrointestinal, cutaneous, disseminated and miscellaneous. This report concerns a previously robust farmer who suffered from left upper lung abscess caused by Rhizopus spp.-one member of the order Mucorales. Initially, it was intended to administer amphotericin B to a total dose of 2,000 mg; however, the patient could not tolerate such side effects as nausea, vomiting and refused further management when the cumulative dose was 948 mg. However, he did recover without further fever and cough. Chest X-ray, followed every three months, disclosed satisfactory improvement.

Amphotericin B↗
PubMed1995

Legionnaires' disease with acute renal failure: report of two cases.

Acute renal failure in Legionnaires' disease is rare, but the mortality rate is high [1-3]. Although the actual pathogenesis is not clear, the renal pathology discloses either acute tubulointerstitial nephritis or acute tubular necrosis in most cases [3]. We report two cases of Legionnaires' disease complicated by acute renal failure. One patient was completely healthy before, and the other had underlying gouty arthritis and diabetes mellitus. Their renal function was normal before these episodes. The diagnosis of Legionella infection was proved by the indirect fluorescent antibody test on paired sera. After erythromycin treatment, both patients survived. One patient required long-term maintenance hemodialysis, and the other recovered to only mild azotemia after a follow-up period of 5 months. Including our cases, only 55 patients have been reported to have Legionella-induced acute renal failure. This is a rare and serious complication of Legionnaires' disease. Early recognition and treatment is mandatory.

Acute Kidney Injury↗
PubMed1995

Psoas abscess due to mucinous cystadenocarcinoma of the appendix: a case report.

Psoas muscle abscess is an uncommon and challenging entity. The present report describes a 64-year-old man presenting with right flank mass. Abdominal computerized tomography showed a right psoas abscess. Extraperitoneal drainage was performed, and pathology revealed metastatic mucinous adenocarcinoma. After further study, laparotomy and right hemicolectomy were performed under the impression of colon cancer. The final pathology showed mucinous cystadenocarcinoma of appendix. The literature about the etiology, diagnosis and treatment of psoas abscess are reviewed. Additionally, the treatment and prognosis for mucinous cystadenocarcinoma of the appendix are noted.

Appendiceal Neoplasms↗
PubMed1995

Do immunosuppressants cause posttransplant diabetes mellitus?

BACKGROUND: Posttransplant diabetes mellitus (PTDM) was originally described by Starzl in 1964. The incidence is around 3-46%, according to several reports. Etiologies and risk factors of PTDM have been discussed after it was described and recognized as a complication of renal transplantation. METHODS: Twenty-five consecutive renal transplants in 24 recipients were reviewed, and 3 cases of posttransplant diabetes mellitus were found. Cyclosporine A (CsA), Azathioprine (Aza) dose and maintenance dose of Prednisolone (Pred.), rejection episodes, total dosage of steroid used at the time of acute rejection were carefully recorded and analyzed. RESULTS: The mean age of 3 living-related and 22 cadaveric transplant recipients was 32.7 +/- 7.5 and 33.5 +/- 6.8 years in PTDM and non-PTDM patients, and the onset of PTDM was, on the average, 11.3 +/- 10.6 months. Comparative studies between non-PTDM and PTDM groups showed that age, rejection episodes, total dose of methylprednisolone used in acute rejection, CsA level, and dosage of CsA, Aza and prednisolone at 1,6,12 and 24 months were not significantly different from one another. CONCLUSIONS: No significant risk factors or definitive mechanism involved in the development of PTDM were identified in this study. It is suggested that immunosuppressants are involved in the occurrence of PTDM, and probably neither a single factor is responsible nor is dose dependency involved.

Adult↗
PubMed1994

Shape complementarity at protein-protein interfaces.

A matching algorithm using surface complementarity between receptor and ligand protein molecules is outlined. The molecular surfaces are represented by "critical points," describing holes and knobs. Holes (maxima of a shape function) are matched with knobs (minima). This simple and appealing surface representation has been previously described by Connolly [(1986) Biopolymers, Vol. 25, pp. 1229-1247]. However, attempts to implement this description in a docking scheme have been unsuccessful (e.g., Connolly, ibid.). In order to decrease the combinatorial complexity, and to make the execution time affordable, four critical hole/knob point matches were sought. This approach failed since some bound interfaces are relatively flat and do not possess four critical point matches. On the otherhand, matchings of fewer critical points require a very time-consuming, full conformational (grid) space search [Wang, (1991) Journal of Computational Chemistry, Vol. 12, pp. 746-750]. Here we show that despite the initial failure of this approach, with a simple and straightforward modification in the matching algorithm, this surface representation works well. Out of the 16 protein-protein complexes we have tried, 15 were successfully docked, including two immunoglobulins. The entire molecular surfaces were considered, with absolutely no additional information regarding the binding sites. The whole process is completely automated, with no manual intervention, either in the input atomic coordinate data, or in the matching. We have been able to reach this level of performance with the hole/knob surface description by using pairs of critical points along with their surface normals in the calculation of the transformation matrix. The success of this approach suggests that future docking methods should use geometric docking as the first screening filter.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1994

Three-dimensional, sequence order-independent structural comparison of a serine protease against the crystallographic database reveals active site similarities: potential implications to evolution and to protein folding.

We have recently developed a fast approach to comparisons of 3-dimensional structures. Our method is unique, treating protein structures as collections of unconnected points (atoms) in space. It is completely independent of the amino acid sequence order. It is unconstrained by insertions, deletions, and chain directionality. It matches single, isolated amino acids between 2 different structures strictly by their spatial positioning regardless of their relative sequential position in the amino acid chain. It automatically detects a recurring 3D motif in protein molecules. No predefinition of the motif is required. The motif can be either in the interior of the proteins or on their surfaces. In this work, we describe an enhancement over our previously developed technique, which considerably reduces the complexity of the algorithm. This results in an extremely fast technique. A typical pairwise comparison of 2 protein molecules requires less than 3 s on a workstation. We have scanned the structural database with dozens of probes, successfully detecting structures that are similar to the probe. To illustrate the power of this method, we compare the structure of a trypsin-like serine protease against the structural database. Besides detecting homologous trypsin-like proteases, we automatically obtain 3D, sequence order-independent, active-site similarities with subtilisin-like and sulfhydryl proteases. These similarities equivalence isolated residues, not conserving the linear order of the amino acids in the chains. The active-site similarities are well known and have been detected by manually inspecting the structures in a time-consuming, laborious procedure. This is the first time such equivalences are obtained automatically from the comparison of full structures. The far-reaching advantages and the implications of our novel algorithm to studies of protein folding, to evolution, and to searches for pharmacophoric patterns are discussed.

Amino Acid Sequence↗
PubMed1994

Molecular surface representations by sparse critical points.

We have defined a molecular surface representation that describes precisely and concisely the complete molecular surface. The representation consists of a limited number of critical points disposed at key locations over the surface. These points adequately represent the shape and the important characteristics of the surface, despite the fact that they are modest in number. We expect the representation to be useful in areas such as molecular recognition and visualization. In particular, using this representation, we are able to achieve accurate and efficient protein-protein and protein-small molecule docking.

Chymotrypsin↗
PubMed1994

Effects of copper concentration on mineral nutrient uptake and copper accumulation in protein of copper-tolerant and nontolerant Lotus purshianus L.

One copper-tolerant and one copper-sensitive inbred line of Lotus purshianus L. derived from a copper mine waste site in Northern California and one inbred line of the same species derived from a pasture next to the mine waste were examined for the effects of excessive copper concentrations on mineral nutrient uptake and accumulation of copper in protein fractions. Plants were grown from seeds for a period of 24 days in a modified Hoagland nutrient solution culture supplemented with 3, 6, and 10 microM copper as copper sulfate. The basal nutrient solution without copper amendment was used as the control treatment. The uptake of Cu found in the roots was 100 times or more than that in the leaves. The root tissue copper concentrations reached a plateau under 6 microM copper treatment. The leaf tissue copper concentrations increased with the increase of copper concentration in the solution culture. No difference in pattern of copper uptake was detected between the copper-tolerant and nontolerant plants. The effects of excessive copper concentrations caused reduction of Ca uptake in the leaf tissue and P uptake in both the root and leaf tissues, and no difference was found between the copper-tolerant and nontolerant plants. Increased tissue copper concentration caused greater reduction of Fe, Mn, and Zn uptake in the nontolerant plants than in the tolerant plants; this difference may be important for the growth of the tolerant plants under conditions of excessive copper concentrations. Protein extracted from the roots and leaves of both the copper tolerant and nontolerant plants was subjected to Sephadex G-75 column separation. Two major peaks of protein fractions were detected. Under low (normal level) copper concentration treatment, the copper-tolerant and nontolerant plants had similar Cu/protein ratios. However, under high copper concentration challenged conditions the copper-tolerant plant had a considerably greater Cu/protein ratio (peak II protein) than the nontolerant plants. The amino acid composition of the copper-rich protein fraction (peak II) extracted from both the tolerant and nontolerant plants demonstrated a high asparate (about 25%) content. The contents of glutamate, cystine, and glycine were about 11, 2.5, and 10%, respectively, and the rest of the amino acids were in a range of 2 to 6%. This pattern of amino acid composition is different from the amino acid composition of the phytochelatin metallothionein-like proteins found in copper-tolerant plants which are very high in cysteine.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗