LOMETS2: improved meta-threading server for fold-recognition and structure-based function annotation for distant-homology proteins

The LOMETS2 server (https://zhanglab.ccmb.med.umich.edu/LOMETS/) is an online meta-threading server system for template-based protein structure prediction. Although the server has been widely used by the community over the last decade, the previous LOMETS server no longer represents the state-of- the-art due to aging of the algorithms and unsatisfactory performance on distant-homology template identification. An extension of the server built on cutting-edge methods, especially techniques developed since the recent CASP experiments, is urgently needed. In this work, we report the recent advancements of the LOMETS2 server, which comprise a number of major new developments, including (i) new state-of-the-art threading programs, including contact-map-based threading approaches, (ii) deep sequence search-based sequence profile construction and (iii) a new web interface design that incorporates structure-based function annotations. Large-scale benchmark tests demonstrated that the integration of the deep profiles and new threading approaches into LOMETS2 significantly improve its structure modeling quality and template detection, where LOMETS2 detected 176% more templates with TM-scores >0.5 than the previous LOMETS server for Hard targets that lacked homologous templates. Meanwhile, the newly incorporated structure-based function prediction helps extend the usefulness of the online server to the broader biological community.