Molecular systems bound together through noncovalent interactions are ubiquitous in nature, many of which are involved in essential life processes, yet little is known about the principles governing their structure, stability, and function. Cooperativity as one of the intrinsic properties in these systems plays a key role. In this work, on the basis of our recent quantification scheme of the cooperativity effect, we present a general pattern to identify which systems are positively cooperative and which are negatively cooperative. We show that cooperativity in homogeneous molecular systems is positive, but cooperativity in charged molecular systems is negative. We also employ analytical tools from energetics and information perspectives to appreciate the origin of the cooperativity effect. We find that positive cooperativity is dominated by the exchange–correlation interaction and steric effect, whereas negative cooperativity is governed by the electrostatic interaction. Our results should have strong implications for better understanding molecular recognition, protein folding, signal transduction, allosteric regulation, and other processes.

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