A Generic Program for Multistate Protein Design

Some protein design tasks cannot be modeled by the traditional single state design strategy of finding a sequence that is optimal for a single fixed backbone. Such cases require multistate design, where a single sequence is threaded onto multiple backbones (states) and evaluated for its strengths and weaknesses on each backbone. For example, to design a protein that can switch between two specific conformations, it is necessary to to find a sequence that is compatible with both backbone conformations. We present in this paper a generic implementation of multistate design that is suited for a wide range of protein design tasks and demonstrate in silico its capabilities at two design tasks: one of redesigning an obligate homodimer into an obligate heterodimer such that the new monomers would not homodimerize, and one of redesigning a promiscuous interface to bind to only a single partner and to no longer bind the rest of its partners. Both tasks contained negative design in that multistate design was asked to find sequences that would produce high energies for several of the states being modeled. Success at negative design was assessed by computationally redocking the undesired protein-pair interactions; we found that multistate design's accuracy improved as the diversity of conformations for the undesired protein-pair interactions increased. The paper concludes with a discussion of the pitfalls of negative design, which has proven considerably more challenging than positive design

Trends in template/fragment-free protein structure prediction

Predicting the structure of a protein from its amino acid sequence is a long-standing unsolved problem in computational biology. Its solution would be of both fundamental and practical importance as the gap between the number of known sequences and the number of experimentally solved structures widens rapidly. Currently, the most successful approaches are based on fragment/template reassembly. Lacking progress in template-free structure prediction calls for novel ideas and approaches. This article reviews trends in the development of physical and specific knowledge-based energy functions as well as sampling techniques for fragment-free structure prediction. Recent physical- and knowledge-based studies demonstrated that it is possible to sample and predict highly accurate protein structures without borrowing native fragments from known protein structures. These emerging approaches with fully flexible sampling have the potential to move the field forward

Modeling of biochemical networks via classification and regression tree methods

In the description of biological networks, a number of modeling approaches has been suggested based on different assumptions. The major problems in these models and their associated inference approaches are the complexity of biological systems, resulting in high number of model parameters, few observations from each variable in the system, their sparse structures, and high correlation between model parameters. From recent studies, it has been seen that the nonparametric methods can ameliorate these challenges and be one of the strong alternative approaches. Furthermore, it has been observed that not only the regression type of nonparametric models but also nonparametric clustering methods whose calculations are adapted to the biochemical systems can be another promising choice. Hereby, in this study, we propose the classification and regression tree (CART) method as a new approach in the construction of the complex systems when the system’s activity is described under its steady-state condition. Basically, CART is a classification technique for highly correlated data and can be represented as the nonparametric version of the generalized additive model. In this work, we use CART in the construction of biological modules and then networks. We analyze the performance of CART comprehensively under various Monte Carlo scenarios such as different data distributions and dimensions. We compare our results with the outputs of the Gaussian graphical model (GGM) which is the most well-known model under the given condition of the system. In our study, we also evaluate the performance of CART with the GGM findings by using real systems. For this purpose, we choose the pathways which have a crucial role on the cervical cancer. In the analyses, we consider this particular illness since it is the second most common cancer type in women both in Turkey and in the world after the breast cancer, and there is only a limited information for the description of this complex system disease