loop. It exits in four calcium binding states: a doubly loaded state(a state with a calcium atom in each of its two binding sites), two singly loaded states (a state with calcium in its first binding site only and a state with calcium in its second binding site) and an apo-state (a state with no calcium atom). Experiments have shown that calcium binding occurs in a positive cooperative fashion. This fact is also supported by computational studies on dynamics of backbone of the protein. Studies of the methyl side chain dynamics of the doubly loaded state of the protein by molecular dynamics simulation further enhances the point. To further investigate by computation, the molecular dynamics simulation approach has been used to study the side chain dynamics of all four calcium binding states of the protein. In the study, the different kinds of force fields, especially the AMBER (a molecular dynamics simulation suit)force fields, and different kinds of water models are employed in the GPU environment. 3081-Pos Board B773 An Allosteric Signaling Pathway of Human 3-Phosphoglycerate Kinase Zoltan Palmai 1 , Christian Seifert 2 , Frauke Gra ¨ter 2 , Erika Balog 3 . 1 E ´ cole Polytechnique $ Department of Biology, Palaiseau, France, 2 Heidelberger Institut fu ¨r Theoretische Studien gGmbH, Heidelberg, Germany, 3 Semmelweis University, Budapest, Hungary. 3-Phosphoglycerate kinase (PGK) catalyzes the phospho-transfer reaction be- tween 1,3-bisphosphoglycerate and ADP. It is a two domain enzyme, with the two substrates bound to the two separate domains. In order to perform its function the enzyme has to undergo a large conformational change involving a hinge bending to bring the substrates into close proximity. The allosteric pathway from the open non-reactive state of PGK to the closed reactive state as triggered by substrate binding has only been partially uncovered by experi- mental studies. Here we describe a complete allosteric pathway, which con- nects the substrate binding sites to the interdomain hinge region using Molecular Dynamics simulations combined with Force Distribution Analysis (FDA). While previously identified key residues involved in PGK domain closure are part of this pathway, we here fill the numerous gaps in the pathway by identifying newly uncovered residues and interesting candidates for future mutational studies. 3082-Pos Board B774 Enhanced Sampling of the Catalytic Domain of the Adenyl Cyclase CyaA from Bordetella Pertussis Isidro Cortes Ciriano 1 , Guillaume Bouvier 1 , Michael Nilges 1 , Luca Maragliano 2 , Therese E Malliavin 1 . 1 Structural Bioinformatics, Institut Pasteur, Paris, France, 2 Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy. The catalytic domain (AC) of the CyaA adenyl cyclase toxin of Bordetella pertussis undergoes a conformational transition from the inactive (calmod- ulin-free) to the active (calmodulin-bound) conformation upon binding to calmodulin. In the structure of the complex between AC and the C terminal lobe of calmodulin (C-CaM) elucidated by X-ray crystallography (Guo et al, EMBO J, 24:3190, 2005), AC displays an elongated shape. On the contrary, the calmodulin-free inactive conformation has been only qualitatively charac- terized as more globular by hydrodynamics measurements (Karts et al, Biochemistry, 49:318, 2010). To better understand at the molecular level the conformational transition of AC from the active to the inactive conformation, we introduce here a variant of the Temperature Accelerated Molecular Dynamics (TAMD, Maragliano and Vanden-Eijnden, Chem Phys Lett, 426:168, 2006), the soft-ratcheting TAMD (sr-TAMD). TAMD is a an enhanced sampling method designed to explore the free energy surface associated to a set of variables describing the process under study. In sr-TAMD, a soft-ratcheting criterion (Perilla et al, J Comput Chem, 32:196, 2011) IS introduced to accept values of collective var- iables proposed at each step of TAMD. Hence, the sr-TAMD allows us to drive the sampling of the AC conformational space to those regions where the protein displays a more globular shape. The resulting conformations were further clustered using Self-organizing Maps (Bouvier et al, Bioinformatics, 26:53,2010), allowing us to identify intra-protein hydrogen bonds specific of the appearance of the compact conformations. 3083-Pos Board B775 Synthesis and Modeling of Novel a-Aminoalkylphosphonate Ester Deriva- tives as Potent Inhibitors of Prostate-Specific Antigen; A Comparison Study Arben Kojtari, Haifeng Ji. Chemistry, Drexel University, Philadelphia, PA, USA. Prostate cancer is one of the most prevalent cancers diagnosed in adult males. Described as an omnipresent illness, it is believed that the diagnosis is inevi- table for men as life expectancy increases worldwide. Clinically, a diagnosis of prostate cancer is determined by measuring quantitatively prostate-specific antigen (PSA) protein in blood serum. It has been implicated that high PSA concentrations in blood plasma is a biomarker for not only prostate cancer but also the metastasis of the tumor cells into the bone and lymph nodes via IGFBP-3/IGF-I & -II and TGF-b pathways. Although the precise role of PSA in carcinogensis and tumor progression is currently disputed, compounds specific towards PSA binding have been synthesized towards understanding the molecular mechanisms of the protease and inhibiting its proteolytic activity. Here, we describe the mechanism of a-aminoalkylphosphonate ester deriva- tives as potent irreversible inhibitors of PSA. Autodock4.2 molecular dynamics package was utilized to model covalent and non-covalent binding of this class of inhibitors to predict crystallographic poses and compare experimental IC50 dose-response curves and in silico potencies for future rational drug design research. The study not only introduces aminoalkylphosphonates as a potential drug candidate for targeting PSA, but also provides insight to drug binding and validation of Autodock4.2 in future drug development using quantitative structure-activity relationships. 3084-Pos Board B776 Molecular Dynamics Studies: The Effect of Phosphorylation in Saccharide Transporter System Jumin Lee, Wonpil Im. Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, USA. Saccharides have a crucial role in our body not only as nutrition but also as recognition markers by forming glycoconjugates. Thus, the transport of absorbed saccharides into the cell is important to maintain the vital activity of all living organisms. In bacteria, saccharides are transported into cytosol through the cell membrane by phosphoenolpyruvate-dependent sugar phospho- transferase system (PTS). Before the saccharides release into the cell, the sac- charides are phosphorylated by phospho-transferase, and the phosphorylation prevents the saccharides from diffusing back across their transporter. The crys- tal structure of the membrane protein EIIC, which is the most important compo- nent of phosphotransferase, was identified by Zhou, et al. (2011) However, the transport mechanism of saccharides remains unclear. In this study, we explore the effect of the phosphorylation in the saccharide transport system by using all-atom molecular dynamics simulations. To investigate the effect of the phos- phorylation, we performed three simulations with no saccharide, saccharide, and phosphorylated saccharide in the binding sites. Thus, the simulations sug- gest that the phosphate group of phosphorylated saccharide affects the confor- mations of the gate region, resulting in opening the gate of EIIC. This study provides insights into the saccharide transport mechanism, and it could be a base for finding the reasonable mechanism of the saccharide transport and further experiments. 3085-Pos Board B777 Comparison of Metrics of Inter-Structure Distance When Applied to Molecular Dynamics Simulations of Intrinsically Disordered Proteins Robert L. Wang 1 , Timothy G. Connolly 2 , Joshua L. Phillips 3 , Amanda V. Miguel 4 , Ajay Gopinathan 2 , Shawn D. Newsam 1 , Michael E. Colvin 2 . 1 School of Engineering, UC Merced, Merced, CA, USA, 2 School of Natural Sciences, UC Merced, Merced, CA, USA, 3 Los Alamos National Laboratory, Los Alamos, NM, USA, 4 Stanford University, Stanford, CA, USA. Intrinsically disordered proteins (IDPs) exist in a naturally unfolded state con- sisting of a vast ensemble of transient conformations. Molecular dynamics (MD) simulations of IDPs are capable of estimating subsets of these ensembles, but most current tools to analyze MD trajectories are optimized to study protein simulations sampling relatively small conformational spaces. The commonly used measurement, root-mean-square deviation (RMSD), appears to saturate to maximal distance within tens to hundreds of nanoseconds in simulations of highly disordered proteins. Furthermore, in paired structures with inter- structure distances near the saturation of the RMSD measurement, the fits to the reference structures were sometimes meaningless. We have created and validated several tools based on the libraries and interface of the MD simulation software Gromacs 4 [Hess, et al. 2008]. In addition, we have completed a library which implements ten metrics of inter-structure distance. The metrics that we have investigated include modifications to the RMSD metric, various comparisons of backbone angles and dihedrals, calculations of correlation coefficients based on coordinates and shape, and two additional metrics of structure comparisons based on recent publications: MAMMOTH [Ortiz, et al. 2002] and elastic shape analysis [Liu, et al. 2011]. We will present a com- parison of metric saturation as well as the performance of these metrics in differentiating protein simulations by mean conformational differences. We 610a Tuesday, February 18, 2014