Molecular Modeling By Rashmi Shrivastava Lecturer School of Biotechnology Devi Ahilya University, Indore

Scope and aim of molecular modeling Accurate prediction of structure from the sequence. To provide the basis of structure- based drug design, analysis of protein functions, interactions, antigenic behavior, rational design of proteins with increased stability or novel function

Methods of Modeling Homology Modeling- The easiest one. Based on the observations that -the structure of protein is uniquely determined by its amino acid sequence. during evolution the structure is more stable and changes at a much slower rate than the associated sequence, So that similar sequences adopt practically identical structures Homology modeling can be used when there is a clear relation (> 30 % identity) between the sequence of a protein of unknown structure to that of a sequence of a known structure, most likely to be found in Protein Data Bank (PDB, a database of solved protein structures).

Threading When there is no recognizable sequence similarity it involves threading a specific sequence through all known folds and, for each fold, estimating the probability that the sequence can have that fold. Threading or the fold recognition approach is based on the fact that apparently unrelated proteins adopt similar folds. To generate sequence- structure alignments 1D-3D profiles are constructed

Ab initio Free energy considerations to obtain low energy minima Conformational space searching It may help in genome wide modeling

Homology Modeling Template selection- BLAST Downloading structure file from PDB Model Building- Modeller Generate atom file- .atm from PDB Generate alignment file- .aln file Generate a script file to give running parameters

Alignment file

Script file in Python

Result files 1fdx.B00001 1fdx.D000001 1fdx.V000001

Model Optimization Select best model- based on conformational features and energy Optimize by minimization of energy Discover CHARMM

Model Validation Use Procheck, ERRAT, VERIFY 3D and energy