A Comparison Between Elastic Network Interpolation and MD Simulation of 16S Ribosomal RNA

Abstract

In this paper a coarse-grained method called elastic network interpolation (ENI) is used to generate feasible transition pathways between two given conformations of the core central domain of 16S Ribosomal RNA (16S rRNA). The two given conformations are the extremes generated by a molecular dynamics (MD) simulation, which differ from each other by 10Å in root-mean-square deviation (RMSD). It takes only several hours to build an ENI pathway on a 1.5GHz Pentium with 512 MB memory, while the MD takes several weeks on high-performance multi-processor servers such as the SGI ORIGIN 2000/2100. It is shown that multiple ENI pathways capture the essential anharmonic motions of millions of timesteps in a particular MD simulation. A coarse-grained normal mode analysis (NMA) is performed on each intermediate ENI conformation, and the lowest 1% of the normal modes (representing about 40 degrees of freedom (DOF)) are used to parameterize fluctuations. This combined ENI/NMA method captures all intermediate conformations in the MD run with 1.5Å RMSD on average. In addition, if we restrict attention to the time interval of the MD run between the two extreme conformations, the RMSD between the closest ENI/NMA pathway and the MD results is about 1Å. These results may serve as a paradigm for reducedDOF dynamic simulations of large biological macromolecules as well as a method for the reduced-parameter interpretation of massive amounts of MD data.     

IWS: integrated web server for protein sequence and structure analysis

Rapid increase in protein sequence information from genome sequencing projects demand the intervention of bioinformatics tools to recognize interesting gene-products and associated function. Often, multiple algorithms need to be employed to improve accuracy in predictions and several structure prediction algorithms are on the public domain. Here, we report the availability of an Integrated Web-server as a bioinformatics online package dedicated for in-silico analysis of protein sequence and structure data (IWS). IWS provides web interface to both in-house and widely accepted programs from major bioinformatics groups, organized as 10 different modules. IWS also provides interactive images for Analysis Work Flow, which will provide transparency to the user to carry out analysis by moving across modules seamlessly and to perform their predictions in a rapid manner. AVAILABILITY: IWS IS AVAILABLE FROM THE URL: http://caps.ncbs.res.in/iws.     

High-throughput modeling and analysis of protein structural dynamics

Protein function is a dynamic property closely related to the conformational mechanisms of protein structure in its physiological environment. To understand and control the function of target proteins, it becomes increasingly important to develop methods and tools for predicting collective motions at the molecular level. In this article, we review computational methods for predicting conformational dynamics and discuss software tools for data analysis. In particular, we discuss a high-throughput, web-based system called iGNM for protein structural dynamics. iGNM contains a database of protein motions for more than 20 000 PDB structures and supports online calculations for newly deposited PDB structures or user-modified structures. iGNM allows dynamics analysis of protein structures ranging from enzymes to large complexes and assemblies, and enables the exploration of protein sequence-structure-dynamics-function relations.     

Relation between sequence and structure of HIV-1 protease inhibitor complexes: a model system for the analysis of protein flexibility.

The flexibility of different regions of HIV-1 protease was examined by using a database consisting of 73 X-ray structures that differ in terms of sequence, ligands or both. The root-mean-square differences of the backbone for the set of structures were shown to have the same variation with residue number as those obtained from molecular dynamics simulations, normal mode analyses and X-ray B-factors. This supports the idea that observed structural changes provide a measure of the inherent flexibility of the protein, although specific interactions between the protease and the ligand play a secondary role. The results suggest that the potential energy surface of the HIV-1 protease is characterized by many local minima with small energetic differences, some of which are sampled by the different X-ray structures of the HIV-1 protease complexes. Interdomain correlated motions were calculated from the structural fluctuations and the results were also in agreement with molecular dynamics simulations and normal mode analyses. Implications of the results for the drug-resistance engendered by mutations are discussed briefly.