Ensembles, CodonTest, Volumetric Analysis

http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000911
Evidence of Functional Protein Dynamics from X-Ray Crystallographic Ensembles

There is a well-recognized gap between the dynamical motions of proteins required to execute function and the experimental techniques capable of capturing that motion at the atomic level. We show that much experimental detail of dynamical motion is already present in X-ray crystallographic data, which arises from being solved by different research groups using different methodologies under different crystallization conditions, which then capture an ensemble of structures whose variations can be quantified on a residue-by-residue level using local density correlations. We contrast the amino acid displacements below and above the protein dynamical transition temperature, TD∼215K, of hen egg white lysozyme by comparing the X-ray ensemble to MD ensembles as a function of temperature. We show that measuring structural variations across an ensemble of X-ray derived models captures the activation of conformational states that are of functional importance just above TD and they remain virtually identical to structural motions measured at 300K. It provides a novel analysis of large X-ray ensemble data that is useful for the broader structural biology community.

Jonathan E. Kohn1, Pavel V. Afonine2, Jory Z. Ruscio1, Paul D. Adams1,2, Teresa Head-Gordon1,2*

1 Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America, 2 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America


http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000885
Wayne Delport1, Konrad Scheffler2, Gordon Botha2, Mike B. Gravenor3, Spencer V. Muse4, Sergei L. Kosakovsky Pond5*

1 Department of Pathology, University of California, San Diego, La Jolla, California, United States of America, 2 Computer Science Division, Department of Mathematical Sciences, Stellenbosch University, Stellenbosch, South Africa, 3 School of Medicine, University of Swansea, Swansea, United Kingdom, 4 Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America, 5 Department of Medicine, University of California, San Diego, La Jolla, California, United States of America


VASP: A Volumetric Analysis of Surface Properties Yields Insights into Protein-Ligand Binding Specificity
Brian Y. Chen1,2, Barry Honig1,2*

1 Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, United States of America, 2 Howard Hughes Medical Institute, Columbia University, New York, New York, United States of America
Many algorithms that compare protein structures can reveal similarities that suggest related biological functions, even at great evolutionary distances. Proteins with related function often exhibit differences in binding specificity, but few algorithms identify structural variations that effect specificity. To address this problem, we describe the Volumetric Analysis of Surface Properties (VASP), a novel volumetric analysis tool for the comparison of binding sites in aligned protein structures. VASP uses solid volumes to represent protein shape and the shape of surface cavities, clefts and tunnels that are defined with other methods. Our approach, inspired by techniques from constructive solid geometry, enables the isolation of volumetrically conserved and variable regions within three dimensionally superposed volumes. We applied VASP to compute a comparative volumetric analysis of the ligand binding sites formed by members of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains and the serine proteases. Within both families, VASP isolated individual amino acids that create structural differences between ligand binding cavities that are known to influence differences in binding specificity. Also, VASP isolated cavity subregions that differ between ligand binding cavities which are essential for differences in binding specificity. As such, VASP should prove a valuable tool in the study of protein-ligand binding specificity.