Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Enhanced sampling of peptides and proteins with a new biasing replica exchange method
Classical MD simulations (cMD) are limited by the sampling of relevant states of the peptides. Replica exchange (REMD) methods aim to search the conformational space of proteins more efficiently [reviewed in Ostermeir & Zacharias, 2013]. We have developed a Hamiltonian REMD method that takes advantage of an intrinsic property of proteins, the specific ɸ φ dihedral angle combinations along the polymer backbone. By employing a coupled 2 dimensional biasing potential the energy barriers along the polymer backbone are reduced more effectively than by a previous approach based on a 1D biasing potential [Kannan & Zacharias, 2007]. Thus adjacent amino acids along the polymers backbone can easily switch between favorable regions in the Ramachandran plot. Additionally energy barriers of rotameric states of amino acid side chains of proteins are also biased in the replica runs. The method improves the sampling of conformational substates of proteins at a modest number of replicas (9 replicas in the standard setup with one replica running without biasing potential) compared to much larger numbers necessary in case of standard temperature (T)-REMD simulations. A further improvement is achieved by a dynamical adjustment of the penalty potential levels in the replicas such that high exchange rates and improved mixing of conformations between different replicas are guaranteed. The biasing potential (BP)-REMD method turns out to be suitable to speed up both the folding of spaghetti-like test peptides and the refinement of loop decoy structures. Starting form extended structures an α-helical oligo-alanine and the β-hairpin chignolin and the Trp-cage protein fold more rapidly in near- native structures than in cMD simulations. The BP-REMD simulations do not only accelerate the folding process of test proteins but also enlarge the variety of sampled configurations in conformational space. Since flexible parts of the protein can be penalized selectively, this method provides and precise tool to investigate regions of interest of the protein.
S. Kannan, M. Zacharias.(2007). Enhanced sampling of peptide and protein conformations using replica exchange simulations with a peptide backbone biasing-potential. Proteins 66, 697–706.
Physics Department T38