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The 64 amino acid hirudin‐like peptide HM2 (Hirudinaria manillensis) is one of the agents known to specifically block the blood‐clotting enzyme thrombin, and therefore is used as a potential pharmacological tool for the treatment of arterial and venous thrombosis. This peptide and its derivatives provide a new set of probes for studies aimed at elucidating the structural basis of the inhibition of α‐thrombin. We used 581, 699, and 492 nmr‐derived constraints respectively in a protocol employing simulated annealing, followed by restrained molecular dynamics and restrained energy minimization to derive the three‐dimensional structures of HM2 and its mutants the HM2(V + G) and the HM2(1–47). HM2 consists of a well‐defined core region of two double‐stranded β‐sheet and a disordered C‐terminus. These features are shared by other members of the hirudin family. The same type of folding has also been observed for recombinant hirudins whose structure has been determined in solution by nmr spectroscopy and in the structure of the complex hirudin‐thrombin determined by x‐ray diffraction. Molecular dynamics (MD) simulation methods were applied in the study of the structural and dynamic fluctuation properties of the hirudin derivatives solvated by 1625 and 1276 water molecules with periodic boundary conditions for HM2 and HM2(1–47), respectively. Trajectories of 100 and 50 ps for the two unconstrained systems were generated at constant temperature and pressure. Analysis of the MD simulation shows that the structure of the peptide core is fairly rigid and stable in itself while the conformation of the C‐terminal tail, which is involved in the inhibitory mechanism of thrombin, fluctuates and appears as a disordered region. © 1997 John Wiley & Sons, Inc. Biopoly 41: 731–749, 1997

The relationships between atomic hardness, atomic electronegativity, and electronic energy are considered and emphasized. A new method for calculating atomic hardness is described. The concept of local hardness is quantified through the calculation of a new variable named alfahardness. Atomic hardness and alfahardness are used for the calculation of both the mean molecular and local properties. The results obtained are discussed and a comparison made with the analogous quantities presented by Pearson. An algorithm has been realized and transformed into a computer routine for use within a CAOS program.

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