Servers and Software

ANMPathway server: Avisek Das and Sunhwan Jo from the Roux lab at the University of Chicago developed this webserver for delivering a conformational transition pathway between two stable states of a protein. The server implements the ANMPathway method developed in collaboration with Mert Gur, Mary Hongying Cheng and Ivet Bahar of the University of Pittsburgh and featured in a recent paper by Das et al. The input information for the webserver are two PDB files corresponding to the end states of a conformational transition along with some parameters and the primary output is the pathway in the form of a PDB file with multiple frames. The method constructs a coarse-grained (CG) model of the protein by replacing each residue with one CG bead placed at the C^α atom of each residue. The energy surface describing the motion of the protein is approximated by a simple two-state potential constructed from the anisotropic network models (ANMs) defined around the input structures of the two end points. By construction, the potential has a cusp hypersurface in the configuration space. The minimum energy structure on this cusp hypersurface is regarded as the “transition state’’ or the highest energy structure along the transition pathway. The method has two main steps: 1) finding the transition state structure on the cusp hypersurface and 2) generating a pathway by combining two separate steepest descent energy minimizations on the two ANM surfaces starting from the transition state. The presence of the cusp hypersurface does not alter most qualitative features of the pathway. The server is extremely efficient; it can generate a pathway for a ~1000 residue protein in an hour depending on the input parameters. Full description of the method as well as applications to several membrane protein systems can be found in the paper.
CHARMM-GUI Ligand Binder module: With the partial support of the MPSDC’s Computational Modeling Core, the group of Wonpil Im was able to complete the CHARMM-GUI Ligand Binder module. Ligand Binder provides standardized CHARMM input files for calculations of absolute binding free energies using the Advanced free energy perturbation molecular dynamics (FEP/MD) simulations. A number of features are implemented to conveniently setup the FEP/MD simulations in highly customizable manners, thereby permitting an accelerated throughput of this important class of computations while decreasing the possibility of human errors.
Continuum-Molecular Dynamics (CTMD) software: Sayan Mondal at the Harel Weinstein lab at Weill Cornell Medical College, Cornell University developed this stand-alone application which implements the hybrid Continuum-Molecular Dynamics (CTMD) approach to compute membrane deformations profiles around multi-segment proteins and corresponding energetics, featured in a recent paper by Mondal et al. (2011). The CTMDapp software calculates the deformation profiles of the bilayer and the free energy cost of the membrane deformation around multi-segment transmembrane proteins, taking into account the radially non-uniform hydrophobic surface of the protein. As the primary input it requires a molecular dynamics trajectory of a multi-segment, transmembrane protein embedded in a bilayer. To allow for calculations without a molecular dynamics input, the CTMDapp software also implements a simplified version of the CTMD method that can assess the radial asymmetry of the membrane-protein interface for a particular protein structure at an approximate level. Methodological details can be found in the original paper. In addition, the application is documented with brief usage notes at every step and generates diagnostic intermediate output.
Crystallographic, Cryo-EM, and Model Refinement: The Godzilla Computing Cluster at the University of Chicago developed an automated software to refine crystallographic, EM, and NMR structures. The server converts moderate- to low-resolution structures at initial (e.g., backbone trace only) or late stages of refinement to structures with increased numbers of hydrogen bonds, improved crystallographic R-factors, and superior backbone geometry. The fully automated method is applicable to DNA-binding and membrane proteins of any size and will aid studies of structural biology by improving model quality and saving considerable effort. It can be applied to the entire structure or just specific regions, and employed multiple times in conjunction with other refinement tools. It can be used with or without electron density. Ref. Haddadian, et al. (2011). Automated real-space refinement of protein structures using a realistic backbone move set. Biophys. J. 101, 899. The method was used in Krishnamurthy, H. & Gouaux, E. (2012) Nature 481, p469; Scharf et al. (2010) Immunity 33, p853; Feld et al. (2010) Nat Struct Mol Biol 17, p1383.
LBT (lanthanide-binding tag) webserver: Aashish Adhikari from Tobin Sosnick’s group at the University of Chicago has created a fully automated webserver for the prediction of LBT insertions onto existing protein structures. The underlying method uses a coarse-grained backbone+Cβ representation of the protein and samples on the backbone dihedral angles. The method predicts the proper conformation of the LBT tag with respect to the parent protein in existing fusion crystal structures. On multiple membrane protein systems, the method’s prediction of feasibility of LBT insertion on various sites qualitatively agree with the experimental data. The method currently reports several metrics to assess the quality of LBT insertion in a specific site in a parent protein. We expect the method to serve as a useful computational tool for experimentalists by helping them select reasonable sites in a given parent protein where the LBT insertion will likely be successful.
GAAMP: General Automated Atomic Model Parameterization: All-atom force fields are mathematical objects constructed from simple analytical functions parameterized to approximate the Born-Oppenheimer potential energy surface and reproduce known experimental observables. Parameters for the all-atom additive non-polarizable potential functions are currently available for amino acids, nucleic acids and common phospholipids. But accurate potential functions are also required for a growing number of novel molecules. Benoît Roux’s group at the University of Chicago has developed this Force Field Server for automatically generating testing and validating the all-atom nonpolarizable force fields used in MD simulations based on quantum mechanical (QM) calculations. XSEDE users may access a GAAMP gateway that takes advantage of the power of XSEDE computing resources.
NAMD: Scalable Molecular Dynamics: NAMD, recipient of a 2002 Gordon Bell Award, is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD was developed by Klaus Schulten‘s Theoretical and Compulational Biophysics group at the University of Illinois at Urbana-Champaign.
ProDy: Protein Dynamics Analysis in Python: ProDy is a free and open-source Python package for analyzing protein structural dynamics. It allows for quantitative analysis of heterogeneous experimental structural datasets and comparison with theoretically predicted conformational dynamics. It is designed and developed by Ahmet Bakan in Ivet Bahar‘s lab at the University of Pittsburgh.
SERCA Pathways: Ion pumps are integral membrane proteins responsible for transporting ions against concentration gradients across biological membranes. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), a member of the P-type ATPases family, transports two calcium ions per hydrolyzed ATP molecule via an “alternating-access” mechanism. While X-ray crystallography provides high-resolution snapshots about the stable experimentally resolved states of the transport cycle, it is very difficult to detect the short-lived intermediate conformations occurring transiently during the transport cycle. Computational methods can be used to help supplement the missing information by providing atomic models for the transient intermediates along the transport cycle. Our goal with the present effort was to elucidate the details of the alternating access mechanism in SERCA by simulating the large-scale conformational transitions between the experimentally resolved stable sates.
SNPS: Symmetric Nano-Positioning System: SNPS combines resonance energy transfer measurements with numerical methods to map 3D positions of a target site in functional homomeric proteins, enabling quantitative analysis of 3D conformational changes. Stand-alone programs for SNPS analysis (and simulation) were developed by H. Clark Hyde from Francisco Bezanilla’s group at the University of Chicago. The SNPS method was recently published as a featured article by Hyde et al. (2012).
VMD: Molecular Visualization Tools: VMD is a molecular visualization program for displaying, animating, and analyzing large biomolecular systems using 3-D graphics and built-in scripting. VMD was developed by Klaus Schulten‘s Theoretical and Compulational Biophysics group at the University of Illinois at Urbana-Champaign.