Lecture 6

Molecular mechanics; Monte Carlo algorithms; Comparative modelling; Side chain modelling

Aims

• To introduce the terms used in calculating a molecule's potential energy.
• To introduce Monte Carlo methods, the Metropolis criterion, and simulated annealing.
• To introduce HSSP-curves and multiple alignments.
• To introduce comparative modelling and its main steps.
• To introduce the side chain modelling problem problem.

Objectives

After this lecture you will be able to:

• discuss some of the terms used in calculating a molecule's potential energy;
• describe Monte Carlo methods and simulated annealing.
• describe how sequence identity and structure similarity are related;
• discuss the main steps in comparative modelling;
• describe the side chain modelling problem problem.

Supplementary Material

Some of the lecture slides are available on-line (1 per page, 4 per page).

Michael Levitt has produced some excellent lecture slides that include descriptions of the protein folding problem, molecular simulation and structure prediction by energy minimisation. Levitt has also written about the history of computational structural biology:

Levitt, M. (2001) The birth of computational structural biology. Nature Structural Biology, 8, 392-393 (doi:10.1038/87545)

including the first applications of protein energy minimisation:

Levitt, M. and Lifson, S. (1969) Refinement of protein conformations using a macromolecular energy minimization procedure. J. Mol. Biol., 46, 269-279 (doi:10.1016/0022-2836( 69)90421-5)

There is an on-line description of simulated annealing and the Metropolis algorithm at:

Carr, Roger "Simulated Annealing." From MathWorld--A Wolfram Web Resource, created by Eric W. Weisstein. http://mathworld. wolfram.com/SimulatedAnnealing.html

HSSP-curves were proposed by Sander, C. and Schneider, R. (Database of homology-derived protein structures and the structural meaning of sequence alignment. Proteins, 9, 56-68, 1991, doi:10.1002/prot.340090107) and were revised by: Rost, B. (Twilight zone of protein sequence alignments. Protein Eng., 12, 85-94, 1999. doi:10.1093/protein/12.2.85)

Several of the figures shown in the lecture were taken from Professional gambling. This is an updated version of the article: R.Rodriguez, R. and Vriend, G. (1997) "Professional gambling", in Vergoten, G. and Theophanides, T. (eds.) Proceedings of the NATO Advanced Study Institute on Biomolecular Structure and Dynamics: Recent Experimental and Theoretical Advances.

A short discussion of techniques in protein structure prediction, and their applications, is given in:

Baker, D., and Sali, A. (2001) Protein structure prediction and structural genomics. Science, 294, 93-96 (doi:10.1126/science.1065659)