Computational prediction of membrane protein (MP) structures is very challenging partially due to lack of sufficient solved structures for homology modeling. Recently direct evolutionary coupling analysis (DCA) sheds some light on protein contact prediction and accordingly, contact-assisted folding, but DCA is effective only on some very large-sized families since it uses information only in a single protein family. This paper presents a deep transfer learning method that can significantly improve MP contact prediction by learning contact patterns and complex sequence-contact relationship from thousands of non-membrane proteins (non-MPs). Tested on 510 non-redundant MPs, our deep model (learned from only non-MPs) has top L/10 long-range contact prediction accuracy 0.69, better than our deep model trained by only MPs (0.63) and much better than a representative DCA method CCMpred (0.47) and the CASP11 winner MetaPSICOV (0.55). The accuracy of our deep model can be further improved to 0.72 when trained by a mix of non-MPs and MPs. When only contacts in transmembrane regions are evaluated, our method has top L/10 long-range accuracy 0.62, 0.57, and 0.53 when trained by a mix of non-MPs and MPs, by non-MPs only, and by MPs only, respectively, still much better than MetaPSICOV (0.45) and CCMpred (0.40). All these results suggest that sequence-structure relationship learned by our deep model from non-MPs generalizes well to MP contact prediction. Improved contact prediction also leads to better contact-assisted folding. Using only top predicted contacts as restraints, our deep learning method can fold 160 and 200 of 510 MPs with TMscore>0.6 when trained by non-MPs only and by a mix of non-MPs and MPs, respectively, while CCMpred and MetaPSICOV can do so for only 56 and 77 MPs, respectively. Our contact-assisted folding also greatly outperforms homology modeling.
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