Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways.

Simulations can provide tremendous insight into the atomistic details of biological mechanisms, but micro- to millisecond timescales are historically only accessible on dedicated supercomputers. We demonstrate that cloud computing is a viable alternative that brings long-timescale processes within reach of a broader community. We used Google's Exacycle cloud-computing platform to simulate two milliseconds of dynamics of a major drug target, the G-protein-coupled receptor β2AR.

Relaxation of backbone bond geometry improves protein energy landscape modeling.

A key issue in macromolecular structure modeling is the granularity of the molecular representation. A fine-grained representation can approximate the actual structure more accurately, but may require many more degrees of freedom than a coarse-grained representation and hence make conformational search more challenging. We investigate this tradeoff between the accuracy and the size of protein conformational search space for two frequently used representations: one with fixed bond angles and lengths and one that has full flexibility.

NMR structure of a gemcitabine-substituted model Okazaki fragment.

Gemcitabine (2'-deoxy-2',2'-difluorodeoxycytidine; dFdC) is a potent anticancer drug that exerts cytotoxic activity, in part, through incorporation of the nucleoside triphosphate dFdCTP into DNA and perturbations to DNA-mediated processes. The structure of a model Okazaki fragment containing a single dFdC substitution, [GEM], was determined using NMR spectroscopy and restrained molecular dynamics to understand structural distortions that may be induced in replicating DNA resulting from dFdC substitution. The electrostatic surface of [GEM] was also computed to determine how the geminal difluoro group of dFdC perturbs DNA electrostatics.

The Ensemble/Legacy Chimera extension: standardized user and programmer interface to molecular Ensemble data and Legacy modeling programs.

Ensemble/Legacy is a toolkit extension of the Object Technology Framework (OTF) that exposes an object oriented interface for accessing and manipulating ensembles (collections of molecular conformations that share a common chemical topology) and driving Legacy programs (such as MSMS, AMBER, X-PLOR, CORMA/MARDIGRAS, Dials and Windows, and CURVES). Ensemble/Legacy provides a natural programming interface for running Legacy programs on ensembles of molecules and accessing the resulting data. Using the OTF reduces the time cost of developing a new library to store and manipulate molecular data and also allows Ensemble/Legacy to integrate into the Chimera visualization program.

Virtual network computing: cross-platform remote display and collaboration software.

VNC (Virtual Network Computing) is a computer program written to address the problem of cross-platform remote desktop/application display. VNC uses a client/server model in which an image of the desktop of the server is transmitted to the client and displayed. The client collects mouse and keyboard input from the user and transmits them back to the server.

Shape-selective recognition of a model Okazaki fragment by geometrically-constrained bis-distamycins.

Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated in aggressive malignancies. Structural studies have indicated a bend occurs in the helical axis at the junction region (JR) that joins the DNA duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki fragments. To identify a structural motif that provides a shape complementary to the Okazaki fragment minor groove, we have investigated the binding of geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA], with a sequence derived from the genome of simian virus 40 (SV40).

Restrained molecular dynamics of solvated duplex DNA using the particle mesh Ewald method.

Restrained and unrestrained aqueous solution molecular dynamics simulations applying the particle mesh Ewald (PME) method to DNA duplex structures previously determined via in vacuo restrained molecular dynamics with NMR-derived restraints are reported. Without experimental restraints, the DNA decamer, d(CATTTGCATC).d(GATGCAAATG) and trisdecamer, d(AGCTTGCCTTGAG).

Effect of cytarabine on the NMR structure of a model okazaki fragment from the SV40 genome.

Okazaki fragments occur as intermediates during lagging strand DNA replication. Alterations in Okazaki fragment structure may contribute to the anticancer activities of nucleoside analogues such as cytarabine, a potent anti-leukemic agent that inhibits lagging strand replication. We have determined the solution structures for two model Okazaki fragments, [OKA] and [ARAC].