Molecular Dynamics Simulations and Analysis of ABC Transporters

Anthony   M.   George; Peter   M.   Jones

Abstract

The increasing availability of atomic-level protein structures derived from X-ray crystallography and NMR spectroscopy, together with advances in computational power, have ushered in a new era of powerful theoretical approaches to study protein mechanisms and, by extension, use a computer-aided structural approach to drug design. Classical molecular dynamics calculations, in which Newtons equations of motion are solved for all atoms in the system, has emerged as an important tool for analysing protein dynamics at physiologically relevant timescales, in ways that are either very difficult or impossible to do experimentally. Indeed, the computer is becoming a kind of virtual microscope that can observe things not observable by any other means. The availability of more sophisticated parallel computer clusters and program suites will lead to simulations that will be capable of examining entire processes such as polypeptide folding pathways and reaction mechanisms. In this review, the incipient application of molecular dynamics analysis of ABC (ATPBinding Cassette) transporters is surveyed and discussed, with particular relevance to unresolved and controversial issues.

Keywords: ABC transporter, molecular dynamics simulations, nucleotide-binding domain, HisP, MsbA, BtuCD, structurebased drug design