Based on a query of "bioinformatics && year:2010" to Citeulike and some html parsing, the top 10 papers published in 2010 on bioinformatics are, in decreasing order of number of libraries containing the article:

56 - Wooley, J. C., A. Godzik, and I. Friedberg (2010, February). A Primer on Metagenomics. PLoS Comput Biol 6(2), e1000667+. http://www.citeulike.org/group/14230/article/6734445

51 - Searls, D. B. (2010, June). The Roots of Bioinformatics. PLoS Comput Biol 6(6), e1000809+. http://www.citeulike.org/group/14230/article/7358340

44 - Moore, J. H., F. W. Asselbergs, and S. M. Williams (2010, February). Bioinformatics challenges for genome-wide association studies. Bioinformatics (Oxford, England) 26(4), 445-455. http://www.citeulike.org/group/14230/article/6497618

36 - Li, H. and N. Homer (2010, September). A survey of sequence alignment algorithms for next-generation sequencing. Briefings in Bioinformatics 11(5), 473-483. http://www.citeulike.org/group/14230/article/7157821

35 - Goecks, J., A. Nekrutenko, J. Taylor, and The Galaxy Team (2010, August). Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences. Genome Biology 11(8), R86+. http://www.citeulike.org/group/14230/article/7706897

32 - Schadt, E. E., M. D. Linderman, J. Sorenson, L. Lee, and G. P. Nolan (2010, September). Computational solutions to large-scale data management and analysis. Nature Reviews Genetics 11(9), 647-657. http://www.citeulike.org/group/14230/article/7677964

30 - Horner, D. S., G. Pavesi, T. Castrignana, P. D. De Meo, S. Liuni, M. Sammeth, E. Picardi, and G. Pesole (2010, March). Bioinformatics approaches for genomics and post genomics applications of next-generation sequencing. Briefings in Bioinformatics 11(2), 181-197. http://www.citeulike.org/group/14230/article/6021372

29 - Navlakha, S. and C. Kingsford (2010, April). The power of protein interaction networks for associating genes with diseases. Bioinformatics 26(8), 1057-1063. http://www.citeulike.org/group/14230/article/6725425

28 - Jelizarow, M., V. Guillemot, A. Tenenhaus, K. Strimmer, and A.-L. Boulesteix (2010, August). Over-optimism in bioinformatics: an illustration. Bioinformatics 26(16), 1990-1998. http://www.citeulike.org/group/14230/article/7363255

27 - Rebholz-Schuhmann, D., S. Kavaliauskas, and P. Pezik (2010, April). PaperMaker: validation of biomedical scientific publications. Bioinformatics 26(7), 982-984. http://www.citeulike.org/group/14230/article/6760711

A quick summary suggest that most folks think metagenomics, genome-wide association studies, next-generation sequencing, reproducible research, large scale data management, interaction networks, validation, and text-mining are topics to watch.

The latest issue of Nature Biotechnology contains the article Trends in computational biology—2010. Summary:

Interviews with leading scientists highlight several notable breakthroughs in computational biology from the past year and suggest areas where computation may drive biological discovery.

I suggest you visit the Faculty of 1000 to find the most ranked articles in this field. For example, one of the 'best' article is http://www.ncbi.nlm.nih.gov/sites/entrez/20887892

Cell. 2010 Oct 1;143(1):46-58. Long noncoding RNAs with enhancer-like function in human cells.

Russ Altman's round-up of important papers in bioinformatics for 2010 from his annual “Year in Review” talk to the AMIA Translational Bioinformatics Summit can be found here.

Maybe you could turn it around. Instead of picking the best paper on computational biology, you could consider the best paper in your field of expertise of which you value the ideas presented as enrichment to the field of computational biology.