Approximately 20 leading scientists will attend this workshop to discuss the "state of the field" with respect to designing novel proteins and enzymes. These scientists represent a broad range of expertise: Some specialize in computational design of novel proteins, while others focus on evolutionary and combinatorial methods for selection and optimization. The purpose of the workshop will be threefold: (i) To describe how contributions from different disciplines have enabled enormous recent advances in our ability to devise novel proteins that fold and function; (ii) To discuss the potential for future developments in this field, and describe how cross-fertilization between disciplines can enhance this progress; and (iii) To explicitly discuss challenges and/or roadblocks that might impede this progress, and to propose approaches that will enable researchers to overcome these challenges in the coming decade. The workshop will focus on both basic science and real-world applications of protein design, engineering, and selection.
Summary of Meeting: Twenty two scientists were invited to participate in a workshop on the Design, Engineering, and Selection of Novel Proteins. The participants are leaders in theirs fields and were chosen to represent a broad range of expertise: Some specialize in computational design of novel proteins, while others focus on evolutionary and combinatorial methods for selection and optimization. In addition to the invited researchers, Program Directors and other personnel from the NSF also attended the workshop. The workshop focused both on past accomplishments and future goals. First, the participants assessed the advances of recent years, and discussed how early challenges were overcome. Second, and perhaps more importantly, the participants considered where the field is heading in the coming years, what future challenges might arise, and how these challenges might be overcome. Suggestions to Enhance Future Progress: Beyond merely summarizing the state of current research, the goal of the workshop was to discuss where the field is going, and how to overcome challenges that may impede progress. These issues were discussed in breakout sessions, and summarized by representatives from each subgroup. These summaries stimulated discussions with the entire group of participants, which led to the following suggestions to stimulate and fund future progress in the Design, Engineering, and Selection of Novel Proteins: 1. Multi-disciplinary collaborations: Multi-disciplinary workshops. Cross-disciplinary training. Support people, not just instruments: 2. High throughput structural and functional characterization: A protein structure initiative aimed at de novo proteins. High throughput functional assays. 3. Advancing computational methods. Loop design. Design of buried polar residues. Computational approaches to calculate energies of solvation. Modeling explicit water. Computational methods that deal with dynamic structures. Assessment of structure quality. Methods that merge statistical modeling with structural modeling. 4. Novel proteins and novel chemistries: Membrane proteins. Metals in biology. Novel backbones and non-natural side chains. Novel cofactors. Novel reactions Future work in the area will include novel proteins composed of non-natural amino acids and non-peptide backbones, which fold into novel 3-dimensional structures, bind non-natural cofactors, and catalyze non-biological reactions. 5. Novel methods for library construction, screening, and selection: Library construction. Novel screens and selections. Combining the need for novel methods of screening and selecting, with the inclusion of novel chemistries. Extracting data from large libraries. Robotics. 6. Data Repositories for benchmarking iterative designs: A database containing both successful and failed designs: Data repositories for experimental results. Catalogues and repositories for de novo proteins. 7. Big Picture questions about natural proteins and the design of novel proteins: Are proteins special? Are natural sequences special? What is the relationship between structure and function? Do we understand molecular evolution? How do new functions arise in protein structures that were hitherto inactive? How can we select functions that do not exist in nature and for which biological selections are not available? How do enzymes become so proficient? Biological Questions: In many cases, evolution seems to have selected higher levels of activity than necessary. Why is this true? Chemical Questions: In some cases, a rational design seems to get everything ‘right,’ yet the enzyme activity is poor. In other cases, randomly selected changes enhance activity dramatically. Which chemical features lead to high-level activity? Broader Impacts of the Field: Designing, engineering, and selecting novel proteins are not merely intellectual exercises. Progress in these areas will have enormous impacts on real-world applications. Biotechnology, as it is practiced today, relies on genes and proteins copied (or modified) from nature. While natural proteins have provided leads for a range of successful biotechnologies, natural sequences are limited to the subset of possible sequences, which are (or were) useful to living organisms. By developing methods to devise novel proteins, we will broaden the feedstock of sequences, structures, and functions that may be useful for technological applications, but which were not useful to living organisms, and therefore not selected by nature. Because sequences will be devised de novo, they will not be biased by eons of selection for biological survival, and may provide activities that differ substantially from those harvested from nature. Because this field is central to our understanding of molecular biology and biochemistry, and crucial for the development of future biotechnologies, the workshop focused both on basic science and on real-world applications of protein design, engineering, and selection.
