Protein dynamics: The future is bright and complicated!

Abstract

Biological life depends on motion, and this manifests itself in proteins that display motion over a formidable range of time scales spanning from femtoseconds vibrations of atoms at enzymatic transition states, all the way to slow domain motions occurring on micro to milliseconds. An outstanding challenge in contemporary biophysics and structural biology is a quantitative understanding of the linkages among protein structure, dynamics, and function. These linkages are becoming increasingly explorable due to conceptual and methodological advances. In this Perspective article, we will point toward future directions of the field of protein dynamics with an emphasis on enzymes. Research questions in the field are becoming increasingly complex such as the mechanistic understanding of high-order interaction networks in allosteric signal propagation through a protein matrix, or the connection between local and collective motions. In analogy to the solution to the “protein folding problem,” we argue that the way forward to understanding these and other important questions lies in the successful integration of experiment and computation, while utilizing the present rapid expansion of sequence and structure space. Looking forward, the future is bright, and we are in a period where we are on the doorstep to, at least in part, comprehend the importance of dynamics for biological function.

Replicating enzymatic activity by positioning active sites with synthetic protein scaffolds

“…41, 42 On the other hand, different protein scaffolds possess distinct inherent protein dynamics, including the atomic local fluctuations and large structure collective motions, which also significantly regulates the intrinsic activity of enzymes. 43 The computational construction of isoenzymes with artificial protein architectures can yield isoenzymes with distinct protein dynamics that are absent in nature. With these isoenzymes we are able to pursue quantitative and mechanistic insights into the relationship between catalysis and protein dynamics.…”

Loop Evolutionary Patterns Shape Catalytic Efficiency of TRI101/201 for Trichothecenes: Insights into Protein–Substrate Interactions

“…This novel finding expands our understanding of enzyme function and engineering, as it differs from conventional factors that influence the protein catalytic activity. 63 Therefore, future efforts to improve the catalytic activity of TRI101/201 should focus on enhancing the flexibility of the loop cover and regulating its interaction with skylight residues.…”

Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development

“…Notable examples of such studies include the Markov state modeling (MSM) studies of cSrc protein kinase, the metadynamics simulations of cyclin-dependent protein kinase 5 and adenylyl cyclase, the string method simulation study of insulin receptor kinase (IRK), and the alchemical free energy simulation study of insulin-like growth factor 1 kinase (IGF-1RK) . However, in contrast to the structure prediction problem, which can be approached using pairwise interactions, allosteric networks are generally orders of magnitude more complex and rely on clusters of interacting networks on multiple levels . In addition, the energetic separation between microscopic structural states in allosteric mechanisms can be minute, on the order of a few “ k B T ”, and therefore difficult to accurately quantify with existing computational approaches and force fields.…”

“…Enzymes differ from conventional catalysts in their ability to accelerate chemical reactions, often exceeding a million-fold. − This unparalleled catalytic power makes them indispensable for carrying out a vast array of biological functions that would not otherwise be possible . However, enzymes are not ordinary catalysts; they exhibit exceptional selectivity in recognizing and binding specific substrates, ensuring efficient catalysis while preventing wasteful or undesirable side reactions. − What further distinguishes enzymes is that they are regulated by multiple and customized mechanisms so that each chemical process occurs with exquisite timing within the relevant cellular context. − Throughout evolution, these unique features of enzymes have exerted evolutionary pressure, resulting in the optimization of their functions and even the development of new capabilities. − In addition, the design of robust enzymes has received considerable attention in recent years .…”