Biophysics Lecture

Natural proteins can fold spontaneously into well-defined three-dimensional structures, and can display complex biochemical properties such as signal transmission, efficient catalysis of chemical reactions, specificity in molecular recognition, and allosteric conformational change. These properties arise from the cooperative action of amino acid residues, but the global pattern of functional interactions between residues in the three-dimensional structure is generally unknown. As a consequence, we do not understand the general rules, if any, in the evolutionary design of proteins. To address this, developed an approach (the statistical coupling analysis or SCA) for estimating the pattern of functional interactions between sites on proteins through statistical analysis of the evolutionary divergence of a protein family1,2. This analysis indicates a novel decomposition of proteins into sparse subsets of co-evolving amino acids that we term protein sectors 9. The sectors are evolutionarily quasi-independent and comprise physically connected networks in the tertiary structure. Experiments in several protein systems demonstrate the functional importance of the sectors 1,3,4,7,8,10,11 and recently, the pattern of constraints emerging from SCA was shown to the necessary and sufficient to design functional artificial members of two protein families in the absence of any structural or chemical information5,6. These results support the hypothesis that sectors represent the basic architecture of functional interactions in natural proteins. We are now working on understanding the physical mechanisms underlying sectors, and perhaps more importantly, trying to understand why sectors might represent a feature of proteins that emerge through the evolutionary process.

[1] Lockless, R. Ranganathan, Science, 286, 295-9 (1999). [2] Suel et al., Nature Struct. Biol., 10., 59-69 (2003). [3] Hatley, et al., PNAS, 100: 14445-14450 (2003). [4] Shulman et al., Cell, 116: 417-429 (2004). [5] Socolich et al., Nature, 437: 512-518 (2005). [6] Russ et al., Nature, 437: 579-583 (2005). [7] Mishra et al., Cell, 131: 80-92 (2007). [8] Lee et al., Science 322: 438-442 (2008). [9] Halabi et al., Cell 138: 774-785 (2009). [10] Smock et al., Mol. Sys. Biol. 6: 414 (2010). [11] Reynolds et al., Cell, 147: 1564-1575(2011).