Modeling enzyme-inhibitor interactions in serine proteases

Abstract

ABSTRACT:We are interested in modeling enzyme᎐inhibitor interactions with a view to improve the understanding of the biology of these processes. The present work focuses, therefore, on the research on enzyme᎐inhibitor interactions using two highly homologous enzymes as our models: ␤-factor XIIa and trypsin. This study so far has Ž . focused on the following: 1 arginine᎐carboxylate interactions such as the one occurring in the ''binding pocket'' of ␤-factor XIIa with an inhibitor; according to the present calculations, the neutral form is usually more stable than is the zwitterion in hydrophobic Ž . environments as in the case of the above-mentioned complex. 2 Interactions present in the contact region between trypsin and PTI; the contribution of some amino acids of that region to the binding energy of the complex trypsin᎐PTI was determined using free-Ž . energy simulation methods. 3 Interactions involved in the inhibition of trypsin by PTI; Ž . hybrid quantum-classical mechanical calculations LSCF were performed to further this point.

Simulation of stochastic hybrid systems with switching and reflecting boundaries

“…SHS models of biochemical systems using reaction rate analysis have been developed and simulated in (Salis and Kaznessis 2005). A biochemical system drug Riley, Koutsoukos, and Riley model based on physical interactions at the molecular level has been developed in (Ramos et al 1999). An early stochastic model of the water/electrolyte balance system is presented in (Leaning et al 1985), and a nonstochastic model with experimental results is presented in (Karanfil 2005).…”

Parametrization of Synthetic Amino Acids

“…Mutations of coded amino acids by noncoded ones can create peptomimetic drugs with high pharmaceutical potential . A further insight into biological properties of peptomimetic drugs can be provided by computer-aided molecular modeling and simulation techniques. − The main limitation to this approach is that the well-established biomolecular force fields such as CHARMM, , AMBER, − and GROMOS do not have parameters for noncoded amino acids. This work reports on the parametrization and validation of a set of parameters, committed to the AMBER force field, for a series of noncoded amino acids.…”

The Mode of Action of Phospholipase A2: Semiempirical MO Calculations Including the Protein Environment

“…In this way protein-environment effects can be included with acceptable computational costs. QM/MM methods have been used successfully for the investigation of enzyme reaction mechanisms by several reasearch groups, [7][8][9][10][11][12][13][14][15][16] and reviews on this topic are available in the literature. [17][18][19] Phospholipase A 2 , the subject of this work, has also been studied previously with QM/MM methods.…”

“…In this way protein-environment effects can be included with acceptable computational costs. QM/MM methods have been used successfully for the investigation of enzyme reaction mechanisms by several reasearch groups, − and reviews on this topic are available in the literature. − …”