Barry's Research

I am interested in the structure, evolution and function of proteins - what they look like, how they have arisen and how they work.

My current work is centered on developing and employing computational techniques to understand basic principles underlying protein function. An ultimate goal is to exploit such information to facilitate the fields of protein design and drug discovery.

Specific areas of current investigation include:

Molecular Motor Proteins

 Molecular motors are the essential agents of movement within living organisms. They allow cells to establish and maintain their complex internal structure by transporting packets of molecular components to localized, and distant, reaction sites. For example they shuffle chromosomes around during cell division, move organelles and neurotransmitters around inside brain cells, help microbes move and cause the motion of muscles.

A principal aim in the study of molecular motors, is a detailed understanding of how chemical energy, derived from the hydrolysis of ATP, is converted into mechanical energy. This process, termend mechanochemical transduction, is thought to involve the amplification of small nucleotide induced conformational changes into larger movements that ultimately drive cellular motility.
Bio3D
I have performed a number of studies on kinesin and myosin motors to probe possible mechanisms for conformational change. These studies have used available sequence and crystal structure data, complemented by structural bioinformatics approaches on motor homologues and analogues (which provide key landmarks in conformational analyses). The simulations are based on an empirically derived potential energy function for the description of inter/intra-molecular interactions. Methods employed include normal mode analysis (for intrinsic mechanical properties); equilibrium and non-equilibrium molecular dynamics (for the response of systems to changes in the nucleotide state), and Brownian dynamics (for diffusional encounters of the motor with its respective track).


Comparative Analysis of Protein Structures

 The detailed comparison of homologous protein structures can be used to infer pathways for evolutionary adaptation and, at closer evolutionary distances, mechanisms for conformational change. Traditionally, such investigations have involved careful visual inspection combined with structural alignment methods. These procedures are both time consuming and labor intensive, and require expert insight into the systems studied. With the growing number of determined protein structures, the availability of automatic procedures for analyzing the differences and similarities between structures becomes increasingly desirable.

I am the lead developer of bio3d, an R package for the exploratory analysis of structure and sequence data. Features of the package include the ability to read and write structure, sequence and dynamic trajectory data, perform atom summaries, atom selection, re-orientation, superposition, rigid core identification, clustering, distance matrix analysis, structure and sequence conservation analysis and principal component analysis. Bio3d takes advantage of the extensive graphical and statistical capabilities of the R environment and thus represents a useful framework for exploratory analysis of structural data.
Bio3D Bio3D

Nicotinic Acetylcholine Receptors

 Nicotinic acetylcholine receptors are ligand-gated ion channels responsible for neurotransmitter-mediated signal transduction at synapses. Binding of neurotransmitter molecules to subunit interfaces in the N-terminal extracellular domain induces structural rearrangements of the membrane-spanning domain permitting the influx of cations. Molecular simulation methods are currently being used to probe how conformational changes might propagate from the ligand-binding site to the pore domain and result in channel gating.

Target Selection in Structural Genomics

 I collaborated in the development of sgTarget, an informatics resource capable of performing target selection through the implementation of a number of sequence analysis protocols. The system enables structural biologists to select targets from their genomic sequences of interest, according to their research needs.

Bio3D


Approaches

Bioinformatics
Develop and employ tools for the analysis of protein sequence and structural data.

Molecular simulation
I routinely use techniques such Molecular Dynamics and Normal Mode Analysis to probe the structure, dynamics and thermodynamics of proteins.

Conformational analysis
Exploring data resulting from molecular simulations and/or database searches using multivariate statistical methods.

Software and algorithm development
Supporting the above approaches.


Recent Publications

Active site-dependent reconfiguration of a tubulin binding subdomain in kinesin.
Grant, McCammon, Caves, Cross (2007) Journal of Molecular Biology ?, Submitted.
( Abstract | PubMed | PDF )

Bio3D: An R package for the comparative analysis of protein structures.
Grant, Rodrigues, ElSawy, McCammon, Caves, (2006) Bioinformatics 22, 2695-2696
( Abstract | PubMed | PDF )

Targeted Molecular Dynamics Study of C-Loop Closure and Channel Gating in Nicotinic Receptors.
Cheng X, Wang H, Grant B, Sine SM, McCammon JA (2006) PLoS Comput Biol 2, No. 9.
( Abstract | PubMed | PDF )

sgTarget: a target selection resource for structural genomics.
Rodrigues AP, Grant BJ, Hubbard RE (2006) Nucleic Acids Res 34, No. Web Server issue.
( Abstract | PubMed | PDF )

Channel Opening Motion of [alpha]7 Nicotinic Acetylcholine Receptor as Suggested by Normal Mode Analysis
Cheng X, Lu B, Grant B, Law RJ, Mccammon AJ (2006) Journal of Molecular Biology 355, No. 2. 310-324.
( Abstract | PubMed | PDF )



Software developed to support my research studies includes:

Bio3D
- a package for protein sequence and structural analysis; and

sgTarget
- a target selection resource for structural genomics.