Method for low resolution prediction of small protein tertiary structure

Conference · Tue Dec 31 04:00:00 EST 1996

OSTI ID:549263

Ortiz, A R; Hu, W P; Kolinski, A; Skolnick, J ^[1]

---

1. Scripps Research Institute, La Jolla, CA (United States)

A new method for the de novo prediction of protein structures at low resolution has been developed. Starting from a multiple sequence alignment, protein secondary structure is predicted, and only those topological elements with high reliability are selected. Then the multiple sequence alignment and the secondary structure prediction are combined to predict side chain contacts. Such contact map prediction is carried out in two stages. First, an analysis of correlated mutations is carried out to identify pairs of topological elements of secondary structure which are in contact. Then, inverse folding is used to select compatible fragments in contact, thereby enriching the number and identity of predicted side chain contacts. The final outcome of the procedure is a set of noisy secondary and tertiary restraints. These are used as a restrained potential in a Monte Carlo simulation of simplified protein models driven by statistical potentials. Low energy structures are then searched for by using simulated annealing techniques. Implementation of the restraints is carried out so as to take into account their low resolution. Using this procedure, it has been possible to predict the de novo structure of three very different protein topologies: an {alpha}/{beta} protein, the bovine pancreatic trypsin inhibitor (6pti), an {alpha}-helical protein, calbindin (3icb), and an all {beta}-protein, the SH3 domain of spectrin (1shg). In all cases, low resolution folds have been obtained with a root mean square deviation (RMSD) of 4.5-5.5 {angstrom} with respect to the native structure. Some misfolded topologies appear in the simulations, but it is possible to select the native one on energetic grounds. Thus, it is demonstrated that the methodology is general for all protein motifs. Work is in progress in order to test the methodology on a larger set of protein structures. 22 refs., 3 figs., 1 tab.

• OSTI ID: 549263
• Report Number(s): CONF-970132--
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
99 GENERAL AND MISCELLANEOUS
ALGORITHMS
AMINO ACID SEQUENCE
ANNEALING
COMPUTERIZED SIMULATION
CONFORMATIONAL CHANGES
CRYSTAL LATTICES
DNA SEQUENCING
ELECTRIC POTENTIAL
ELECTRONIC STRUCTURE
FREE ENERGY
IMPLEMENTATION
MONTE CARLO METHOD
MUTATIONS
PROTEIN STRUCTURE
PROTEINS
RELIABILITY
RESOLUTION
STRUCTURE-ACTIVITY RELATIONSHIPS
THREE-DIMENSIONAL CALCULATIONS
TOPOLOGICAL MAPPING
TRYPSIN