283
Chapter 10
Coarse-Grained Simulation of
Intrinsically Disordered Proteins
David de Sancho, Christopher M. Baker, and Robert B. Best
INTRODUCTION
e important role played by intrinsically disordered proteins (IDPs) in protein–
protein interaction networks and cellular signaling is increasingly being rec-
ognized [1–3]. In these interactions, an intrinsically disordered polypeptide
CONTENTS
Introduction 283
Types of Coarse-GrainedModels Suitable for IDPs 285
Coarse-Grained Modeling of Protein–Protein Interactions 286
Standard Gō Models 287
Modications for the Study of IDPs 289
Local Structural Propensities 289
Nonnative and Electrostatic Interactions 289
Insights into Binding Mechanisms from Coarse-Grained Models 290
Conformational Selection and Induced Fit 292
Beyond Coarse-Grained Models 293
Coarse-Grained Modeling of Protein–Nucleic Acid Interactions 293
Intrinsic Disorder in Nucleic Acid Binding 293
Coarse-Grained Models of DNA 294
Coarse-Grained Models of IDP–DNA Complexes 296
Coupled Folding and Binding in Protein–Nucleic Acid Complexes 296
Intrinsically Disordered Regions Not Directly Involved in Sequence-
Specic Binding 297
Outlook 299
References 299
Coarse-Grained Simulation of Intrinsically Disordered Proteins
284
(often an intrinsically disordered region of a multidomain protein) binds to
another macromolecule, be it a folded protein, another intrinsically disordered
protein, or a nucleic acid. Frequently, but not always, the disordered region
undergoes a local folding transition coupled to binding [2]. A rich variety of
possible binding scenarios is thus generated (in comparison with the simpler
case of two folded proteins associating) and consequently many interesting
questions arise regarding the binding mechanism, the bound state, and pos-
sible advantages of disordered regions versus folded proteins in fullling a
given role in an interaction network [4]. While bioinformatics provides pow-
erful tools for hypothesis testing by correlation [5], it does not provide direct
physical insight into the origin of any observed eects.
Physics-based models do not have this deciency. Fully atomistic simula-
tions of coupled folding-binding with explicit solvent in principle provide the
highest accuracy feasible, albeit requiring large computational resources in
addition to enhanced sampling methods in order to sample binding. However,
there are a number of reasons why atomistic simulations may not be the best
choice for studying folding-binding transitions at the time of writing. e rst
is that the energy functions, or force elds, themselves have some limitations,
which may be particularly detrimental to an accurate treatment of unfolded
or disordered proteins. For example, unfolded states using current protein
force elds and water models are too collapsed and structured in comparison
to any experimental measure [6], and nonspecic protein–protein association
appears to be too favorable [7]. Since this deciency could clearly bias any bind-
ing mechanism obtained in simulation, use of such force elds for studying
coupled folding and binding may be questionable. e second issue relates to
the sort of questions that are being asked. If a set of binding events at atomistic
detail is needed, certainly all atom simulations are the only feasible approach.
However, for a great number of interesting questions, this level of detail is
unnecessary and may even make it harder to identify the eects that are really
important. Lastly, the computational cost for studying binding events, even
with enhanced sampling, is still very high. is limits the possibility of varying
the protein sequence or other conditions in order to test hypotheses. Coarse-
grained simulation models, in which the number of congurational degrees
of freedom as well as the complexity of the energy function are reduced, can
help to overcome some of these deciencies. ey make it easier to tune both
sequence and interactions, and, in some cases, to make accurate predictions of
binding mechanism. eir major drawback is their limited predictive value for
specic cases, particularly if a structure of the bound complex is not known.
Nonetheless, there are many generic and specic questions that can be more
straightforwardly investigated with the aid of coarse-grained models.
In this chapter, we will give an overview of the types of coarse-grained mod-
els that may be useful for investigating intrinsic structure formation as well as

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