title: Attractor Structures of Signaling Networks: Consequences of Different Conformational Barcode Dynamics and Their Relations to Network-Based Drug Design.
abstract: Conformational barcodes tag functional sites of proteins and are decoded by interacting molecules transmitting the incoming signal. Conformational barcodes are modified by all co-occurring allosteric events induced by post-translational modifications, pathogen, drug binding, etc. We argue that fuzziness (plasticity) of conformational barcodes may be increased by disordered protein structures, by integrative plasticity of multi-phosphorylation events, by increased intracellular water content (decreased molecular crowding) and by increased action of molecular chaperones. This leads to increased plasticity of signaling and cellular networks. Increased plasticity is both substantiated by and inducing an increased noise level. Using the versatile network dynamics tool, Turbine (www.turbine.linkgroup.hu), here we show that the 10 % noise level expected in cellular systems shifts a cancer-related signaling network of human cells from its proliferative attractors to its largest, apoptotic attractor representing their health-preserving response in the carcinogen containing and tumor suppressor deficient environment modeled in our study. Thus, fuzzy conformational barcodes may not only make the cellular system more plastic, and therefore more adaptable, but may also stabilize the complex system allowing better access to its largest attractor.
authors.affiliation: Department of Medical Chemistry, Semmelweis University, Tuzolto str. 37-47, H-1094 Budapest, Hungary.
authors.forename: Kristóf Z
authors.initials: KZ
authors.lastname: Szalay
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.|Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Department of Medical Chemistry, Semmelweis University, Tuzolto str. 37-47, H-1094 Budapest, Hungary. peter.csermely@med.semmelweis-univ.hu.
authors.forename: Peter
authors.initials: P
authors.lastname: Csermely
keywords: Adaptation strategies; Attractors; Conformational barcodes; Drug design strategies; Fuzzy systems; Molecular memory; Network dynamics; Network plasticity; Network rigidity