title: Stochastic roadmap simulation for the study of ligand-protein interactions.
abstract: Understanding the dynamics of ligand-protein interactions is indispensable in the design of novel therapeutic agents. In this paper, we establish the use of Stochastic Roadmap Simulation (SRS) for the study of ligand-protein interactions through two studies. In our first study, we measure the effects of mutations on the catalytic site of a protein, a process called computational mutagenesis. In our second study, we focus on distinguishing the catalytic site from other putative binding sites. SRS compactly represents many Monte Carlo (MC) simulation paths in a compact graph structure, or roadmap. Furthermore, SRS allows us to analyze all the paths in this roadmap simultaneously. In our application of SRS to the domain of ligand-protein interactions, we consider a new parameter called escape time, the expected number of MC simulation steps required for the ligand to escape from the 'funnel of attraction' of the binding site, as a metric for analyzing such interactions. Although computing escape times would probably be infeasible with MC simulation, these computations can be performed very efficiently with SRS. Our results for six mutant complexes for the first study and seven ligand-protein complexes for the second study, are very promising: In particular, the first results agree well with the biological interpretation of the mutations, while the second results show that escape time is a good metric to distinguish the catalytic site for five out of seven complexes.
authors.affiliation: Department of Computer Science Department of Biochemistry, Stanford University, CA 94305, USA. apaydin@cs.stanford.edu
authors.forename: Mehmet Serkan
authors.initials: MS
authors.lastname: Apaydin
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Guestrin
authors.forename: Chris
authors.initials: C
authors.lastname: Varma
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Brutlag
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Latombe
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000032:analysis / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000032:analysis / Q000737:chemistry*; D020539:Sequence Analysis, Protein / Q000379:methods*; D013269:Stochastic Processes; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D008024:Ligands; D046912:Multiprotein Complexes; D011506:Proteins