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Title: Active-Site Hydration and Water Diffusion in Cytochrome P450cam: A Highly Dynamic Process

Long-timescale molecular dynamics simulations (300 ns) are performed on both the apo- (i.e., camphor-free) and camphor-bound cytochrome P450cam (CYP101). Water diffusion into and out of the protein active site is observed without biased sampling methods. During the course of the molecular dynamics simulation, an average of 6.4 water molecules is observed in the camphor-binding site of the apo form, compared to zero water molecules in the binding site of the substrate-bound form, in agreement with the number of water molecules observed in crystal structures of the same species. However, as many as 12 water molecules can be present at a given time in the camphor-binding region of the active site in the case of apo-P450cam, revealing a highly dynamic process for hydration of the protein active site, with water molecules exchanging rapidly with the bulk solvent. Water molecules are also found to exchange locations frequently inside the active site, preferentially clustering in regions surrounding the water molecules observed in the crystal structure. Potential-of-mean-force calculations identify thermodynamically favored trans-protein pathways for the diffusion of water molecules between the protein active site and the bulk solvent. Binding of camphor in the active site modifies the free-energy landscape of P450cam channels toward favoringmore » the diffusion of water molecules out of the protein active site.« less
Authors:
 [1] ;  [1]
  1. ORNL
Publication Date:
OSTI Identifier:
1037664
DOE Contract Number:
DE-AC05-00OR22725
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biophysical Journal; Journal Volume: 101; Journal Issue: 6
Research Org:
Oak Ridge National Laboratory (ORNL)
Sponsoring Org:
ORNL Program Development
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CAMPHOR; CRYSTAL STRUCTURE; CYTOCHROMES; DIFFUSION; FREE ENERGY; HYDRATION; PROTEINS; SAMPLING; SIMULATION; WATER