computation Review Challenges in the Computational Modeling of the Protein Structure—Activity Relationship Gabriel Del Río Department of Biochemistry and Structural Biology, Institute of Cellular Physiology, UNAM, Mexico City 04510, Mexico; [email protected] Abstract: Living organisms are composed of biopolymers (proteins, nucleic acids, carbohydrates and lipid polymers) that are used to keep or transmit information relevant to the state of these organisms at any given time. In these processes, proteins play a central role by displaying different activities required to keep or transmit this information. In this review, I present the current knowledge about the protein sequence–structure–activity relationship and the basis for modeling this relationship. Three representative predictors relevant to the modeling of this relationship are summarized to highlight areas that require further improvement and development. I will describe how a basic understanding of this relationship is fundamental in the development of new methods to design proteins, which represents an area of multiple applications in the areas of health and biotechnology. Keywords: protein structure; protein function; bijection 1. Proteins: Fundamental Polymers for Biological Systems Biological systems are composed of biopolymers, including nucleic acids, polymers Citation: Del Río, G. Challenges in (e.g., DNA, RNA), carbohydrates (e.g., starch, cellulose), lipids and proteins. All these the Computational Modeling of the biopolymers play critical roles in all the processes associated with life. Biopolymers are Protein Structure—Activity Relationship. Computation 2021, 9, 39. composed of monomers that are linked in a sequential way; for instance, proteins are https://doi.org/10.3390/ composed of amino acids, while nucleic acids are compose of nucleotides and polymers computation9040039 of carbohydrates are composed of different carbohydrate monomers (e.g., starch and cellulose are made of glucose mainly), and a similar situation occurs with lipids. Since each Academic Editor: Rainer Breitling biopolymer is composed of many different monomers, this situation gives rise to an enormous number of different biopolymer sequences. For instance, proteins are composed Received: 4 February 2021 of 20 different amino acids; hence, proteins that include up to 100 monomers of amino Accepted: 20 March 2021 acids will encompass 20100 different protein sequences. Published: 24 March 2021 The information about the state of the system is maintained by these biopolymers, and this is achieved by controlling the presence/activity of these biopolymers. Activity Publisher’s Note: MDPI stays neutral refers to the action that these biopolymers perform, either maintaining a particular morphol- with regard to jurisdictional claims in ogy, transporting cargo or altering the chemical structure of other molecules, among others. published maps and institutional affil- This activity is commonly referred to as function. In this review, I will use the term activity iations. to avoid confusion with the mathematical term function, which I will also use in this review. The flux of information in biological systems that involves all these biopolymers is depicted in Figure1, where proteins are proposed to play a central role. The central dogma in molecular biology [1] is depicted at the bottom of the figure, where the information flux Copyright: © 2021 by the author. goes from DNA to RNA (transcription) and from RNA to proteins (translation). The figure Licensee MDPI, Basel, Switzerland. includes bidirectional arrows to indicate that the information also goes from RNA to DNA This article is an open access article (retro-transcription) and from protein to RNA or DNA (epigenetics); the information flux distributed under the terms and may go from DNA to DNA, from RNA to RNA or from protein to protein, as indicated conditions of the Creative Commons by circular arrows. The other biopolymers (carbohydrates and lipids) are inserted into Attribution (CC BY) license (https:// this flux of information in the top part of the figure. It is relevant to note that proteins creativecommons.org/licenses/by/ participate in any of these fluxes, e.g., protein transcription factors are required for tran- 4.0/). Computation 2021, 9, 39. https://doi.org/10.3390/computation9040039 https://www.mdpi.com/journal/computation Computation 2021, 9, x FOR PEER REVIEW 2 of 11 Computation 2021, 9, 39 2 of 11 pids) are inserted into this flux of information in the top part of the figure. It is relevant to note that proteins participate in any of these fluxes, e.g., protein transcription factors are required for transcription, ribosomal proteins are involved in translation, and the syn- thesis/degradationscription, ribosomal of proteins carbohydrates are involved or lipids in translation, also requires and proteins. the synthesis/degradation of carbohydrates or lipids also requires proteins. Figure 1. Information flux among biopolymers. Figure 1. Information flux among biopolymers. 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