Functionalized ligand-receptor

As an example for an efficient yet quite accurate approximation, in the first part of our contribution we describe a combination of a structure adapted multipole method with a multiple time step scheme (FAMUSAMM — fast multistep structure adapted multipole method) and evaluate its performance. In the second part we present, as a recent application of this method, an MD study of a ligand-receptor unbinding process enforced by single molecule atomic force microscopy. Through comparison of computed unbinding forces with experimental data we evaluate the quality of the simulations. The third part sketches, as a perspective, one way to drastically extend accessible time scales if one restricts oneself to the study of conformational transitions, which arc ubiquitous in proteins and are the elementary steps of many functional conformational motions. 

Once the model of a ligand-receptor complex is built, its stability should be evaluated. Simple molecular mechanics optimization of the putative ligand-receptor complex leads only to the identification of the closest local minimum. However, molecular mechanics optimization of molecules lacks two crucial properties of real molecular systems temperature and, consequently, motion. Molecular dynamics studies the time-dependent evolution of coordinates of complex multimolecular systems as a function of inter- and intramolecular interactions (see Chapter 3). Because simulations are usually performed at nonnal temperature (—300 K), relatively low energy barriers, on the order of kT (0.6 kcal), can... 

Bajetto A, Bonavia R, Barbero S, PiccioU P, Costa A, Elorio T, Schettini G (1999) GUal and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal ceU-derived factor 1. J Neurochem 73 2348-2357... 

Atrophy of the thymus is a consistent finding in mammals poisoned by 2,3,7,8-TCDD, and suppression of thymus-dependent cellular immunity, particularly in young animals, may contribute to their death. Although the mechanisms of 2,3,7,8-TCDD toxicity are unclear, research areas include the role of thyroid hormones (Rozman et al. 1984) interference with plasma membrane functions (Matsumura 1983) alterations in ligand receptors (Vickers et al. 1985) the causes of hypophagia (reduced desire for food) and subsequent attempts to alter or reverse the pattern of weight loss (Courtney et al. 1978 Seefeld et al. 1984 Seefeld and Peterson 1984) and excretion kinetics of biotransformed metabolites (Koshakji et al. 1984). 

Fig. 9.3. Several mechanisms underlie the functional versatility of the ER. The different distributions of the alpha and beta isotypes of ER conditions a first step that warrants distinct functional profiles depending on the higher or lower affinity of the ligand for one or another isotype (upper panel). Then, differentligands generate distinct 3D conformations in the ligand-receptor complex that condition different interaction profiles with the promoters of target genes (lower panel)...

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