Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations

OOSTENBRINK, Chris, Anita DE RUITER, Jozef HRITZ a Nico VERMEULEN. Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations. CURRENT DRUG METABOLISM. SHARJAH: BENTHAM SCIENCE PUBL LTD, 2012, roč. 13, č. 2, s. 190-196. ISSN 1389-2002.

Základní údaje

• Originální název: Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations
• Autoři: OOSTENBRINK, Chris, Anita DE RUITER, Jozef HRITZ a Nico VERMEULEN.
• Vydání: CURRENT DRUG METABOLISM, SHARJAH, BENTHAM SCIENCE PUBL LTD, 2012, 1389-2002.

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Článek v odborném periodiku
• Obor: Genetika a molekulární biologie
• Stát vydavatele: Spojené arabské emiráty
• Utajení: není předmětem státního či obchodního tajemství
• Impakt faktor: Impact factor: 4.405
• Organizační jednotka: Středoevropský technologický institut
• UT WoS: 000300417500007
• Klíčová slova anglicky: Site of metabolism prediction; protein flexibility; molecular docking; molecular dynamics simulations; replica exchange
• Štítky: ne MU
• Příznaky: Mezinárodní význam, Recenzováno

Anotace

As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show remarkable levels of promiscuity. In this work, we try to link this promiscuity to the versatility and malleability of the active site at the hand of examples from our own work. Mainly focusing on the flexibility of protein structures and the presence or absence of water molecules, we establish molecular reasons for observed promiscuity, determine the relevant factors to take into account when predicting binding poses and rationalize the role of individual interactions in the process of ligand binding. A high level of active site flexibility does not only allow for the binding of a large variety of substrates and inhibitors, but also appears to be important to facilitate ligand binding and unbinding.