Olga Scharkoi

Adaptive spectral clustering with application to tripeptide conformation analysis

A decomposition of a molecular conformational space into sets or functions (states) allows for a reduced description of the dynamical behavior in terms of transition probabilities between these states. Spectral clustering of the corresponding transition probability matrix can then reveal metastabilities. The more states are used for the decomposition, the smaller the risk to cover multiple conformations with one state, which would make these conformations indistinguishable. However, since the computational complexity of the clustering algorithm increases quadratically with the number of states, it is desirable to have as few states as possible. To balance these two contradictory goals, we present an algorithm for an adaptive decomposition of the position space starting from a very coarse decomposition. The algorithm is applied to small data classification problems where it was shown to be superior to commonly used algorithms, e.g., k-means. We also applied this algorithm to the conformation analysis of a tripeptide molecule where six-dimensional time series are successfully analyzed.

Adaptive Spectral Clustering for Conformation Analysis

Markov state models have become very popular for the description of conformation dynamics of molecules over long timescales. The construction of such models requires a partitioning of the configuration space such that the discretization can serve as an approximation of metastable conformations. Since the computational complexity for the construction of a Markov state model increases quadratically with the number of sets, it is desirable to obtain as few sets as necessary. In this paper we propose an algorithm for the adaptive refinement of an initial coarse partitioning. A spectral clustering method is applied to the final partitioning to detect the metastable conformations. We apply this method to the conformation analysis of a model tri‐peptide molecule, where metastable β‐ and γ‐turn conformations can be identified.

Conformational analysis of alternariol on the quantum level

With the help of theoretical calculations we explain the phenomenon of nonplanarity of crystalline alternariol. We find out that the different orientations of the hydroxyl groups of alternariol influence its planarity and aromaticity and lead to different twists of the structure. The presence of the intramolecular hydrogen bond stabilizes the planar geometry while the loss of the bond results in a twist of over 14°. This effect is thought to be involved while cutting DNA strands by alternariol.

Predicting sites of cytochrome P450-mediated hydroxylation applied to CYP3A4 and hexabromocyclododecane

This article describes a simple and quick in silico method for the prediction of cytochrome P450 (CYP)-mediated hydroxylation of drug-like compounds. Testosterone and progesterone, two known substrates of CYP3A4, are used to test the method. Further, we apply the procedure to predict sites of hydroxylation of isomers of the flame retardant hexabromocyclododecane by CYP3A4. Within the method, the compound is rotated in the binding pocket of the cytochrome, so that each hydrogen under consideration is placed near the active centre. Afterwards, short molecular dynamics simulations are provided for each step of the rotation. All steps of the simulation are compared concerning the distances between the hydrogens and the active centre and the corresponding energies. The computational results correlate well with experimental results.

Medizin aus dem Computer

ZusammenfassungKleine Moleküle können großen Einfluss auf Stoffwechselprozesse haben. Der computergestützte Wirkstoffentwurf hat zum Ziel, diese kleinen Moleküle derart zu entwickeln, dass sie besonders selektiv und effektiv bestimmte Proteine im Körper adressieren. Im vorliegenden Beitrag wird beschrieben, welche Ideen dem Wirkstoffentwurf zugrunde liegen und wie ein „virtuelles“ Modell für das zu adressierende Protein etabliert wird. Basierend auf diesem Modell kann am Rechner abgeschätzt werden, wie wahrscheinlich vorgegebene Moleküle mit diesem Protein interagieren werden, ohne diese Moleküle dazu chemisch synthetisieren zu müssen. Der moderne, computergestützte Wirkstoffentwurf geht jedoch weit über dieses einfache „Schlüssel-Schloss-Prinzip“ hinaus. Dieser Beitrag informiert daher außerdem über mögliche zukünftige Forschungsfelder und nennt ein erfolgreiches, aktuelles Beispiel des Wirkstoffentwurfs im Bereich der Schmerztherapie.AbstractSmall molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

Medizin aus dem Computer@@@Medicine from the computer

ZusammenfassungKleine Moleküle können großen Einfluss auf Stoffwechselprozesse haben. Der computergestützte Wirkstoffentwurf hat zum Ziel, diese kleinen Moleküle derart zu entwickeln, dass sie besonders selektiv und effektiv bestimmte Proteine im Körper adressieren. Im vorliegenden Beitrag wird beschrieben, welche Ideen dem Wirkstoffentwurf zugrunde liegen und wie ein „virtuelles“ Modell für das zu adressierende Protein etabliert wird. Basierend auf diesem Modell kann am Rechner abgeschätzt werden, wie wahrscheinlich vorgegebene Moleküle mit diesem Protein interagieren werden, ohne diese Moleküle dazu chemisch synthetisieren zu müssen. Der moderne, computergestützte Wirkstoffentwurf geht jedoch weit über dieses einfache „Schlüssel-Schloss-Prinzip“ hinaus. Dieser Beitrag informiert daher außerdem über mögliche zukünftige Forschungsfelder und nennt ein erfolgreiches, aktuelles Beispiel des Wirkstoffentwurfs im Bereich der Schmerztherapie.AbstractSmall molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

Medicine from the computer

ZusammenfassungKleine Moleküle können großen Einfluss auf Stoffwechselprozesse haben. Der computergestützte Wirkstoffentwurf hat zum Ziel, diese kleinen Moleküle derart zu entwickeln, dass sie besonders selektiv und effektiv bestimmte Proteine im Körper adressieren. Im vorliegenden Beitrag wird beschrieben, welche Ideen dem Wirkstoffentwurf zugrunde liegen und wie ein „virtuelles“ Modell für das zu adressierende Protein etabliert wird. Basierend auf diesem Modell kann am Rechner abgeschätzt werden, wie wahrscheinlich vorgegebene Moleküle mit diesem Protein interagieren werden, ohne diese Moleküle dazu chemisch synthetisieren zu müssen. Der moderne, computergestützte Wirkstoffentwurf geht jedoch weit über dieses einfache „Schlüssel-Schloss-Prinzip“ hinaus. Dieser Beitrag informiert daher außerdem über mögliche zukünftige Forschungsfelder und nennt ein erfolgreiches, aktuelles Beispiel des Wirkstoffentwurfs im Bereich der Schmerztherapie.AbstractSmall molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.