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Protein binding specificity versus promiscuity.

ABSTRACT: Interactions between macromolecules in general, and between proteins in particular, are essential for any life process. Examples include transfer of information, inhibition or activation of function, molecular recognition as in the immune system, assembly of macromolecular structures and molecular machines, and more. Proteins interact with affinities ranging from millimolar to femtomolar and, because affinity determines the concentration required to obtain 50% binding, the amount of different complexes formed is very much related to local concentrations. Although the concentration of a specific binding partner is usually quite low in the cell (nanomolar to micromolar), the total concentration of other macromolecules is very high, allowing weak and non-specific interactions to play important roles. In this review we address the question of binding specificity, that is, how do some proteins maintain monogamous relations while others are clearly polygamous. We examine recent work that addresses the molecular and structural basis for specificity versus promiscuity. We show through examples how multiple solutions exist to achieve binding via similar interfaces and how protein specificity can be tuned using both positive and negative selection (specificity by demand). Binding of a protein to numerous partners can be promoted through variation in which residues are used for binding, conformational plasticity and/or post-translational modification. Natively unstructured regions represent the extreme case in which structure is obtained only upon binding. Many natively unstructured proteins serve as hubs in protein-protein interaction networks and such promiscuity can be of functional importance in biology.

SUBMITTER: Schreiber G

PROVIDER: S-EPMC3053118 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Protein binding specificity versus promiscuity.

Schreiber Gideon G Keating Amy E AE

Current opinion in structural biology 20101109 1

Interactions between macromolecules in general, and between proteins in particular, are essential for any life process. Examples include transfer of information, inhibition or activation of function, molecular recognition as in the immune system, assembly of macromolecular structures and molecular machines, and more. Proteins interact with affinities ranging from millimolar to femtomolar and, because affinity determines the concentration required to obtain 50% binding, the amount of different co ...[more]

PMID: 21071205

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Project description:Binding specificity is an important consideration in drug design. An effective drug molecule often must bind with high specificity to its intended target in the body; lower specificity implies the possibility of significant binding to unintended partners, which could instigate deleterious side effects. However, if the target is a rapidly mutating agent, a drug that is too specific will quickly lose its efficacy by not binding well to functional mutants. Therefore, in molecular design, it is crucial to tailor the binding specificity of a drug to the problem at hand. In practice, specificity is often studied on a case-by-case basis, and it is difficult to create general understanding of the determinants of specificity from the union of such available cases. In this work, we undertook a comprehensive, general study of molecular binding with emphasis on understanding the determinants of specificity from a physical standpoint. By extending a theoretical framework grounded in continuum electrostatics and creating an abstracted lattice model that captures key physical aspects of binding interactions, we systematically explored the relationship between a molecule's physical characteristics and its binding specificity toward potential partners. The theory and simulated binding interactions suggested that charged molecules are more specific binders than their hydrophobic counterparts for several reasons. First, the biological spectrum of possible binding characteristics includes more partners that bind equally well to hydrophobic ligands than to charged ligands. Also, charged ligands, whose electrostatic potentials have strong orientational dependence, are more sensitive to shape complementarity than their hydrophobic counterparts. Ligand conformational and orientational flexibility can further influence a charged molecule's ability to bind specifically. Interestingly, we found that conformational flexibility can increase the specificity of polar and charged ligands, by allowing them to greatly lower the binding free energy to a select few partners relative to others. Additionally, factors such as a molecule's size and the ionic strength of the solution were found to predictably affect binding specificity. Taken together, these results, all of which stem from a unified theoretical framework, provide valuable physical insight into the general determinants of binding specificity and promiscuity in a biological environment. The general principles discussed here could prove useful in the design of molecules with tailored specificities, leading to more effective therapeutics.

Project description:Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) - a drug's ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence.

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Protein binding specificity versus promiscuity.

Publications

Protein binding specificity versus promiscuity.

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