1 Rethinking the protein folding problem from a new perspective Jorge A. Vila

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Rethinking the protein folding problem from a new perspective

Jorge A. Vila

IMASL-CONICET, Universidad Nacional de San Luis, Ejército de Los Andes 950, 5700 San

Luis, Argentina.

Abstract

One of the main concerns of Anfinsen was to reveal the connection between the amino acid

sequence and their biologically active conformation. This search gave rise to two crucial questions

in structural biology, namely, why the proteins fold and how a sequence encodes its folding. As to

the why, he proposes a plausible answer, namely, at a given milieu a protein folds into its functional

form -native state- because such structure represents the lowest free-energy minimum among all

feasible conformations -the thermodynamic hypothesis or Anfinsen’s dogma. As to the how, this

remains as an unsolved challenge and, hence, this inquiry is examined here from a new perspective

of protein folding, namely, as an ‘analytic whole’ -a notion proposed by Leibnitz and Kant’s. This

new perspective forces us to discuss in detail why the theoretical force-field-based approaches

have failed in both their ability to predict the three-dimensional structure of a protein accurately

and in their capacity to answer one of the most critical questions in structural biology: how a

sequence encodes its folding. It is worth noting that the problem of accurately determining the

three-dimensional structure of a protein -for a given amino acid sequence- is considered to have

been solved, viz., by either state-of-the-art numerical methods or by experimental methods.

Therefore, the pros and cons of each of these approaches nor a relative comparison of their

precisions will not be discussed here.

There is overwhelming evidence showing that state-of-the-art numerical methods can

predict, with high accuracy, a three-dimensional (3D) structure of a protein (Tunyasuvunakool et

al., 2021; Kryshtafovych et al. 2021; Marx, 2022). In spite of this, how a protein amino-acid

sequence ‘encodes’ its folding -Anfinsen’s challenge- is yet unknown. Consequently, numerous

questions remain to be answered, e.g., an accurate determination of structural and marginal-

stability changes upon protein point-mutations and/or post-translational modifications (Pancotti et

al., 2022; Serpell et al., 2021; Buel et al., 2022). Yet, all the above downsides do not belong to the

state-of-the-art numerical methods alone. Indeed, neither X-ray crystallography, cryogenic

electron-microscopy (Cryo-EM), nor NMR spectroscopy provide an answer to Anfinsen’s

challenge despite all methods needing to know the amino acid sequence in advance. This is

certainly not surprising, because none of these numerical/experimental methods was designed to

answer the question but to provide an accurate prediction/determination of the tridimensional

structure of the protein. Therefore, the search for an accurate answer to the query of how the protein

amino-acid sequence encodes its folding is a problem that transcends the information provided by

any of the existent methods to predict/determine the protein 3D structure. This gives rise to one

fundamental conjecture to solve Anfinsen’s challenge: the protein folding problem should be

conceived as an ‘analytic whole’. This statement arises from Leibniz & Kant’s notion of space

(and time), devised as ‘analytic wholes’, i.e., the one in which “…its priority makes it impossible

to obtain it by the additive synthesis of previously existing entities…” (Gómez, 1998). From this

point of view, methods based mainly on additive pairwise interactions may not give a precise

answer to Anfinsen's challenge because such methods consider the ‘whole’ as a posteriori rather

than as a priori. Therefore, the solution demands solving an n-body problem, with n being the

number of amino acids in the sequence. The latter seems to be a necessary condition to solve the

protein folding problem. This demand for treating the protein folding as an ‘analytic whole’ is

analogous to that needed by numerical/experimental methods aimed at predicting/determining the

protein-tridimensional shape, namely, the existence of the structure as a ‘whole’ as an a priori for

its resolution. All of the above gives rise to the following theoretical thought. For more than ~60

years, the protein folding problem has been unsuccessfully attempted to be solved at the atomic

level, except for a few exceptions (Kussell et al., 2002; Vila et al., 2003; Lindorff-Larsen et al.,

2011), by using (force) ‘fields’ that are defined, beyond details, by an additive sum of pairwise

interactions (Arnautova et al., 2006; Best, 2019). Then, can we conclude that this has been a failure

of the ‘field’ concept? -that is the most influential discovery since Newton's time, which was

crucial for success in formulating physical-major problems like Maxwell's equations, or the theory

of relativity (Einstein & Infeld, 1961). The answer is undoubtedly no, and the reason is the

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1RethinkingtheproteinfoldingproblemfromanewperspectiveJorgeA.VilaIMASL-CONICET,UniversidadNacionaldeSanLuis,EjércitodeLosAndes950,5700SanLuis,Argentina.AbstractOneofthemainconcernsofAnfinsenwastorevealtheconnectionbetweentheaminoacidsequenceandtheirbiologicallyactiveconformation.Thissearchgaveriseto...

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