| 1. |
- Ljungberg, Kajsa B, et al.
(författare)
-
Computational Modelling of Inhibitor Binding to Human Thrombin
- 2001
-
Ingår i: Eur. J. Pharm. Sci.. ; 12:4, s. 441-446
-
Tidskriftsartikel (refereegranskat)abstract
- Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types ofhuman thrombin inhibitors. Far a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms ofmicroscopic interactions of the ligands with the solvated enzyme.
|
|
| 2. |
|
|
| 3. |
- Ljungberg, Kajsa, et al.
(författare)
-
Efficient kernel algorithms for QTL mapping problems
- 2002
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The advent of sophisticated and powerful methods for molecular genetics pushes the need for efficient methods for data analysis. Advanced algorithms are necessary for extracting all possible information from laboriously obtained data sets. We present a general linear algebra framework for QTL mapping, applicable to many commonly used methods, using both linear regression and maximum likelihood estimation. The formulation simplifies future comparisons between and analyses of the methods. We show how the common structure of QTL analysis models can be used to improve the kernel algorithms, drastically reducing the computational effort while retaining the original analysis results. We have evaluated our new algorithms on data sets originating from two large F2 populations of domestic animals. Using an updating approach, we show that 1-3 orders of magnitude reduction in computational demand can be achieved for matrix factorizations. For interval mapping/composite interval mapping settings using a maximum likelihood model, we also show how to use the original EM algorithm instead of the ECM approximation, significantly improving the convergence and introducing an additional reduction in the computational time. The algorithmic improvements makes it feasible to perform analyses previously deemed impractical or even impossible. For example, using the new algorithms it is reasonable to perform permutation testing using exhaustive search on populations of 200 individuals for fully epistatic two-QTL models with a large number of parameters.
|
|
| 4. |
- Ljungberg, Kajsa
(författare)
-
Numerical methods for mapping of multiple QTL
- 2003
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns numerical methods for mapping of multiple quantitative trait loci, QTL. Interactions between multiple genetic loci influencing important traits, such as growth rate in farm animals and predisposition to cancer in humans, make it necessary to search for several QTL simultaneously. Simultaneous search for n QTL involves solving an n-dimensional global optimization problem, where each evaluation of the objective function consists of solving a generalized least squares problem. In Paper A we present efficient algorithms, mainly based on updated QR factorizations, for evaluating the objective functions of different parametric QTL mapping methods. One of these algorithms reduces the computational work required for an important function class by one order of magnitude compared with the best of the methods used by other authors. In Paper B previously utilized techniques for finding the global optimum of the objective function are compared with a new approach based on the DIRECT algorithm of Jones et al. The new method gives accurate results in one order of magnitude less time than the best of the formerly employed algorithms. Using the algorithms presented in Papers A and B, simultaneous search for at least three QTL, including computation of the relevant empirical significance thresholds, can be performed routinely.
|
|
| 5. |
- Ljungberg, Kajsa, et al.
(författare)
-
Simultaneous search for multiple QTL using the global optimization algorithm DIRECT
- 2003
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Motivation: Epistatic interactions are important for quantitative traits. To maximize the power to detect epistatic quantitative trait loci (QTLs), a simultaneous search is necessary. The computational complexity demands that the traditional exhaustive search be replaced by a more efficient global optimization algorithm.Results: We have adapted DIRECT, an algorithm presented in [Jones93], to the problem of simultaneous mapping of two and three QTL. We have compared DIRECT, in terms of accuracy and speed analyzing real data sets, with standard exhaustive search and a genetic algorithm previously used for QTL mapping in two dimensions. In all two- and three-QTL test cases, DIRECT accurately finds the global optimum two to four orders of magnitude faster than when using an exhaustive search, and one order of magnitude faster than when using the genetic algorithm. A search using a model with three fully interacting QTL is finished in six CPU minutes when using DIRECT, while an exhaustive search takes 142 CPU days. Thus three-QTL randomization testing for determining empirical significance thresholds is made feasible by the use of DIRECT. This opens the possibility to thoroughly investigate the power of simultaneous search to detect at least three interacting QTL.Availability: The source code of the prototype implementation is available at http://www.tdb.uu.se/~kl/qtl_software.html.
|
|
| 6. |
- Marelius, J., et al.
(författare)
-
Sensitivity of an Empirical Affinity Scoring Function to Changes in Receptor-Ligand Complex Conformations
- 2001
-
Ingår i: European Journal of Pharmaceutical Sciences. - 0928-0987 .- 1879-0720. ; 14:1, s. 87-95
-
Tidskriftsartikel (refereegranskat)abstract
- A combination of empirical scoring and conformational sampling for ligand bindingaffinity prediction is examined. The behaviour of a scoring function with respect to thesensitivity to conformational changes is investigated using ensembles of structures generated by molecular dynamics simulation. The correlation between the calculated score and the coordinate deviation from the experimental structure is clear for the complex of arabinose with arabinose-binding protein, which is dominated by hydrogen bond interactions, while the score calculated for the hydrophobic complex between retinol and retinol binding protein is rather insensitive to ligand conformational changes. For typical ensembles of stuctures generated by molecular dynamics at 300 K. the variation of the calculated score is considerably smaller than that of the underlying molecular mechanics interaction energies.
|
|
